Method of treating sexual dysfunctions with delta opioid receptor agonist compounds

ABSTRACT

Compositions and methods for treatment of sexual dysfunctions by administering to a subject a pharmaceutical composition comprising a delta opioid receptor agonist in an amount effective to delay the onset of ejaculation in the subject during sexual stimulation.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. Provisional PatentApplication No. 60/345,216 filed on Jan. 2, 2002.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to compositions and methods oftreatment for sexual dysfunctions, and more particularly, to thetreatment of premature ejaculation in male subjects by administration ofdelta receptor agonist compound(s), optionally in combination with otheragents.

[0004] 2. Description of the Related Art

[0005] Premature ejaculation is one of the most common male sexualdysfunctions, estimated to affect up to 40% of men, irrespective of age.Premature ejaculation is defined as a persistent or recurrentejaculation with minimal sexual stimulation before, on or shortly afterpenetration. Although premature ejaculation is common, there is somedisagreement on its precise cause and treatment.

[0006] The reasons for premature ejaculation are generally thought toinclude a malfunction of the repressor center due to the fatigue ofnervous transmission, hypersensitivity of a specific site due to genitaldisorders, hormonal disorders, physical problems and the like. It isbelieved that the premature ejaculation is generally caused by a complexinteraction of the above-mentioned reasons or by a loss of cooperationamong the related sexual nerve centers.

[0007] Premature ejaculation has been treated with psychotherapy anddrug therapy. Psychotherapy requires sexual training for a long periodof time, which involves discussions and cooperation with a physician andthe patient and his partner. However, since psychotherapy necessitates along period of time for the doctor, patient and partner to work togetherin order to be effective, its success rate is low. That is, changes inliving style, external stress, etc., undermine its success such that theproblem is never solved or it reoccurs. Therefore, drug therapy is nowmore widely used since time restrictions are not as great.

[0008] Methods for treating premature ejaculation by systemicadministration of several different antidepressant compounds have beendescribed in U.S. Pat. Nos. 5,151,448 and 5,276,042. However, thesedrugs may not be effective for all patients, and the side effects ofthese drugs can halt treatment or impair patient compliance. Diseasestates or adverse interactions with other drugs may contraindicate theuse of these compounds or require lower dosages that may not beeffective to delay the onset of ejaculation. Additionally, the stigma ofmental illness associated with antidepressant therapy can discouragepatients from beginning or continuing such treatments.

[0009] Administration of the antidepressant fluoxetine has been claimedto treat premature ejaculation (U.S. Pat. No. 5,151,448). However, theadministration of fluoxetine has many undesired aspects. Patients withhepatic or renal impairments may not be able to use fluoxetine due toits metabolism in the liver and excretion via the kidney. Systemicevents during fluoxetine treatment involving the lungs, kidneys or liverhave occurred, and death has occurred from overdoses. In addition, sideeffects of oral fluoxetine administration include hair loss, nausea,vomiting, dyspepsia, diarrhea, anorexia, anxiety, nervousness, insomnia,drowsiness, fatigue, headache, tremors, dizziness, convulsions, sweatingand skin rashes. Fluoxetine interacts with a range of drugs, often byimpairing their metabolism by the liver.

[0010] U.S. Pat. No. 5,276,042 describes the administration ofparoxetine for the treatment of premature ejaculation. Paroxetine ispredominantly excreted in the urine, and decreased doses are recommendedin patients with hepatic and renal impairments. Paroxetine cannot begiven to patients undergoing treatment with a monoamine oxidaseinhibitor. Side effects from oral administration of paroxetine includehyponatremia, asthenia, sweating, nausea, decreased appetite, oropharynxdisorder, somnolence, dizziness, insomnia, tremors, anxiety, impairedmicturition, weakness and paresthesia.

[0011] Other therapies include the application of local anesthetics forblunting the sensitivity of the sexual peripheral nerve. However, localanesthetics, such as lidocaine ointment or spray, may inducevasoconstriction, which may lead to transient erectile failure, and canbe transferred to sexual partners thereby decreasing their sensitivityand pleasure as well.

[0012] Thus, present day drug therapy cannot successfully solve theproblems associated with premature ejaculation. Accordingly there is aneed for a method of treating premature ejaculation that requires nospecialized psychological therapy, can be used conveniently and withoutembarrassment, and does not involve the problems associated with priortherapeutic methods.

SUMMARY OF THE INVENTION

[0013] The present invention relates in one aspect to a method oftreating premature ejaculation by administering to a subject apharmaceutical composition comprising a delta opioid receptor agonist inan amount effective to delay the onset of ejaculation during sexualstimulation. The delta opioid receptor agonist is either peptidic ornon-peptidic. The pharmaceutical formulation may further comprise anadditional active agent, e.g., Viagra® (sildenafil citrate), Prozac®(fluoxetine), vasoactive agents and combination of two or more thereof.

[0014] One aspect of the present invention provides a method fordelaying the onset of ejaculation in a subject during sexual stimulationcomprising administering to the subject an effective amount of at leastone compound of the formulae: (I)

[0015] wherein:

[0016] Ar¹ is a 5- or 6-member carbocyclic or heterocyclic aromatic ringwith atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur and may include thiophenyl, thiazolyl, furanyl,pyrrolyl, phenyl, or pyridyl, and having on a first carbon atom thereofa substituent Y and on a second ring carbon thereof a substituent R¹,

[0017] Y is selected from the group consisting of:

[0018] hydrogen;

[0019] halogen;

[0020] C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl;

[0021] C₁-C₆ haloalkyl;

[0022] C₁-C₆ alkoxy;

[0023] C₃-C₆ cycloalkoxy;

[0024] sulfides of the formula SR⁸ where R⁸ is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, arylalkyl having a C₅-C₁₀ arylmoiety and an C₁-C₆ alkyl moiety, or C₅-C₁₀ aryl;

[0025] sulfoxides of the formula SOR⁸ where R⁸ is the same as above;

[0026] sulfones of the formula SO₂R⁸ where R⁸ is the same as above;

[0027] nitrile;

[0028] C₁-C₆ acyl;

[0029] alkoxycarbonylamino (carbamoyl) of the formula NHCO₂R⁸ where R⁸is the same as above; carboxylic acid, or an ester, amide, or saltthereof;

[0030] aminomethyl of the formula CH₂NR⁹R¹⁰ where R⁹ and R¹⁰ may be thesame or different, and may be hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₂-C₆ hydroxyalkyl, C₂-C₆ methoxyalkyl, C₃-C₆ cycloalkyl,or C₅-C₁₀ aryl, or R⁹ and R¹⁰ together may form a ring of 5 or 6 atoms,the ring atoms selected from the group consisting of N and C;

[0031] carboxamides of the formula CONR⁹R¹⁰ where R⁹ and R¹⁰ are thesame as above, or C₂-C₃₀ peptide conjugates thereof; and

[0032] sulfonamides of the formula SO₂NR⁹R¹⁰ where R⁹ and R¹⁰ are thesame as above;

[0033] Z is selected from the group consisting of:

[0034] hydrogen, hydroxy and carboxy and esters thereof;

[0035] alkoxy-carboxylic acid, —OCH₃COOH, —ORCOOH;

[0036] alkoxy, carboxyalkoxy, hydroxymethyl, and esters thereof; and

[0037] amino, carboxamides and sulfonamides thereof;

[0038] G is carbon or nitrogen;

[0039] R¹ is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl;

[0040] R² is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl;

[0041] R³, R⁴ and R⁵ may be the same or different, and are independentlyselected from hydrogen and methyl, and wherein at least one of R³, R⁴ orR⁵ is not hydrogen, subject to the proviso that the total number ofmethyl groups does not exceed two, or any two of R³, R⁴ and R⁵ togethermay form a bridge of 1 to 3 carbon atoms;

[0042] R⁶ is selected from the group consisting of:

[0043] hydrogen;

[0044] C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl;

[0045] C₃-C₆ cycloalkyl;

[0046] arylalkyl having C₅-C₁₀ aryl and C₁-C₆ alkyl moieties;

[0047] alkoxyalkyl having C₁-C₄ alkoxy and C₁-C₄ alkyl moieties;

[0048] C₂-C₄ cyanoalkyl;

[0049] C₂-C₄ hydroxyalkyl;

[0050] aminocarbonylalkyl having a C₁-C₄ alkyl moiety; and

[0051] R¹²COR¹³, where R¹² is C₁-C₄ alkylene, and R¹³ is C₁-C₄ alkyl orC₁-C₄ alkoxy or hydroxy,

[0052] or R⁶ is

[0053] and Ar² is a 5 or 6-member carbocyclic or heterocyclic aromaticring with atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur, and having on a carbon atom thereof a substituent X,

[0054] wherein X is selected from the group consisting of a halogen(fluorine, bromine, chlorine, iodine), hydrogen, hydroxy and estersthereof, carboxy and esters thereof; C₁-C₄ carboxy alkyl and estersthereof; alkyl carboxylic acid, carboxylic acid, alkoxy, hydroxymethyl,and esters thereof; and

[0055] amino, and carboxamides and sulfonamides thereof; and

[0056] R⁷ is hydrogen or fluorine;

[0057] wherein

[0058] R₁ and R₂, which can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, C₄₋₆cycloalkylalkyl, C₃₋₆ alkenyl, C₃₋₅ alkynyl, aryl, aralkyl or furan-2 or3-yl alkyl or may form together a C₃₋₇ alkyl ring which may beinterrupted by oxygen.

[0059] R₃ and R₄, which can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl, or R₄ is oxygen forming with the carbonatom to which is attached a C═O group;

[0060] R₅ is hydrogen, hydroxy, C₁₋₃ alkoxy, thiol or alkylthio;

[0061] R₆ is phenyl, halogen, NH₂ or a para or meta —C(Z)—R₈ group, inwhich Z is oxygen or sulphur;

[0062] R₈ is C₁₋₈-alkyl, C₁₋₈-alkoxy or NR₉R₁₀, wherein R₉ and R₁₀,which may be the same or different, are hydrogen, straight or branchedC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, aryl oraralkyl,

[0063] or R₆ is a para or meta

[0064]  group

[0065] in which R₁₁ and R₁₂ which may the same or different arehydrogen, straight or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆cycloalkylalkyl, C₃₋₆ alkenyl, aryl, aralkyl or an optionallysubstituted heterocyclic ring, and Z is as defined above; and,

[0066] R₇ is hydrogen, straight or branched C₁₋₈ alkyl or halogen; (III)

[0067] wherein,

[0068] R₁ and R₂, can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, C₄₋₆cycloalkylalkyl, C₃₋₆ alkenyl, C₃₋₅ alkynyl, aryl, aralkyl or furan-2 or3-yl alkyl or may form together a C₃₋₇ alkyl ring which may beinterrupted by oxygen.

[0069] R₃ and R₄, can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl;

[0070] R₅ is hydroxy, C₁₋₆ alkoxy, thiol or alkylthio;

[0071] R₆ is a —C(Z)—R₈ group, wherein Z is oxygen or sulphur, R₈ isC₁₋₈-alkyl, C₁₋₈-alkoxy or NR₉R₁₀, wherein R₉ and R₁₀, which may be thesame or different, are hydrogen, straight or branched C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, aryl or aralkyl,

[0072] or R₆ is

[0073]  group

[0074] wherein R₁₁ and R₁₂ have the same meaning as R₉ and R₁₀ ortogether form an optionally substituted heterocyclic ring and Z is asdefined above, and R₇ is hydrogen, straight or branched C₁₋₈ alkyl orhalogen;

[0075] (IV)

[0076] wherein

[0077] A is Nor C—X

[0078] wherein

[0079] X is H or C₁₋₄ alkyl;

[0080] G is C—Y

[0081] wherein

[0082] Y is H or C₁₋₄ alkyl;

[0083] B is an optional C₁₋₆ hydrocarbyl group, optionally substituted;

[0084] L is an optional C₁₋₆ hydrocarbyl group, optionally substituted;

[0085] and wherein A, B, and L in combination with the N constitute afirst ring structure which has from 5-7 atoms in the ring;

[0086] further wherein:

[0087] either D is H or a C₁₋₁₀ hydrocarbyl group, or D is a C₁₋₁₀hydrocarbyl group linked to B or L to form a second ring structure whichincludes the N of the first ring structure, which second ring structureis fused to the first ring structure and which second ring structure hasfrom 5-7 atoms in the ring;

[0088] E is a phenyl group substituted by at least one or more ofhydroxy, C₁₋₄ alkoxy, or NH₂SO₂ C₁₋₄ alkylene;

[0089] F represents a combination of a phenyl group and a heterocyclicgroup, wherein

[0090] (i) the phenyl group is positioned intermediate (in between) Gand the heterocyclic group;

[0091] (ii) the phenyl group is fused to the heterocyclic group or islinked directly to the heterocyclic group or is attached via a spacergroup to the heterocyclic group, wherein the spacer group is any one ofC₁₋₄ alkylene, carbonyl or SO 2; and

[0092] (iii) the heterocyclic group is substituted by at least one ormore of: a COOH group, a bio-isostere of a COOH group, a biolabile esterderivative of a COOH group, a C₁₋₁₀ hydrocarbyl group comprising one ormore COOH groups, a C₁₋₁₀ hydrocarbyl group comprising one or morebio-isosteres of a COOH group, or a C₁₋₁₀ hydrocarbyl group comprisingone or more biolabile ester derivatives of a COOH group;

[0093] and pharmaceutically acceptable esters and salts of compounds(I)— (IV).

[0094] The pharmaceutical composition of the present invention maycomprises an amount effective to treat sexual dysfunction with at leastone a delta opioid receptor agonist described in the followingreferences, the contents of which are incorporated by reference hereinin their entireity for all purposes:

[0095] Chang et al. U.S. Pat. No. 5,658,908 issued Aug. 19, 1997;

[0096] Chang et al. U.S. Pat. No. 5,681,830 issued Oct. 28, 1997;

[0097] Chang et al. U.S. Pat. No. 5,552,404 issued Sep. 3, 1996;

[0098] Chang et al. U.S. Pat. No. 5,574,159 issued Nov. 12, 1996;

[0099] Chang et al. U.S. Pat. No. 5,854,249 issued Dec. 29, 1998;

[0100] Chang et al. U.S. Pat. No. 5,807,858 issued Sep. 15, 1998;

[0101] Chang et al. U.S. Pat. No. 5,985,880 issued Nov. 16, 1999;

[0102] Chang et al. U.S. Pat. No. 6,300,332 issued Oct. 9, 2001;

[0103] WO 0146263;

[0104] U.S. Pat. No. 6,130,222;

[0105] U.S. Pat. No. 6,187,792;

[0106] WO 0174804;

[0107] WO 9852929;

[0108] WO 0174805; and

[0109] WO 0174806.

[0110] In another aspect of the invention, a pharmaceutical compositionis provided for carrying out the methods of the invention. Thepharmaceutical composition comprises an effective amount of a deltaopioid receptor agonist as provided herein, a pharmacologicallyacceptable carrier, and optionally another active agent. Other types ofcomponents may be incorporated into the composition as well, e.g.,excipients, surfactants, preservatives, stabilizers, chelating agentsand the like, as will be appreciated by those skilled in the art ofpharmaceutical composition preparation and drug delivery.

[0111] Administration of the pharmaceutical composition is carried outwithin the context of a predetermined dosing regime such that the deltaopioid receptor agonist is effective in the treatment of prematureejaculation.

[0112] Delivery of the pharmaceutical compositions may be accomplishedthrough any route effective to provide relief from prematureejaculation, including, oral, rectal, topical, sub-lingual, mucosal,nasal, ophthalmic, subcutaneous, intramuscular, intravenous,transdermal, spinal, intrathecal, intra-articular, intra-arterial,sub-arachnoid, bronchial, lymphatic, transurethral, intracavernosalinjection and urethral suppository administration.

[0113] Yet another aspect of the present invention relates to dampingmale sexual response or diminishing sexual libido in a subject byadministering to the subject in need thereof, an effective amount of adelta opioid receptor agonist.

[0114] Various other aspects, features and embodiments of the inventionwill be more fully apparent from the ensuing disclosure and appendedclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0115]FIG. 1 is a longitudinal cross-sectional view of an electricbipolar rectal probe used for inducing ejaculation, according to oneembodiment of the present invention.

[0116]FIG. 2 illustrates the dependence of ejaculation on theoscillating frequency of the stimulating electricity.

[0117]FIG. 3 illustrates the suppression effects of delta selectiveagonist SNC-80 in delaying electrically stimulated ejaculation.

[0118]FIG. 4 illustrates that the suppression effects of SNC-80 wereabolished by introduction of NTI, a delta opioid receptor antagonist.

DETAILED DESCRIPTION OF THE INVENTION, AND PREFERRED EMBODIMENTS THEREOF

[0119] Delta opioid receptors are present in the central and peripheralnervous systems of many species, including man. The delta opioidreceptor has been identified as having a role in many bodily functions,such as circulatory and pain systems, immunomodulatory activities, andgastrointestinal disorders.

[0120] Agonists are agents that recognize and bind to the deltareceptors thereby affecting biochemical and/or physiological pathways.One of the major neuronal effects of opioid receptor activation isblocking the release and liberation of neurotransmitters. Theneurotransmitter adrenaline is liberated by postganglic sympatheticnerve, which initiates the contraction of smooth muscle surrounding theseminal vesicle and prostate gland that leads to semen emission.Likewise, the parasympathetic nerve liberates a neurotransmitter thatinitiates contraction of the bulbocarvernous muscle surrounding thepenis, which leads to forcible ejection of semen from the urethra. Whilenot wishing to be bound by any specific mechanism of action, it isbelieved that the activation of the delta opioid receptor leads toinhibiting the release of adrenaline or acetylcholine from sympatheticand parasympathetic nerve endings, and consequently prevents smoothmuscle from contraction with a concomitant delay of ejaculation. It isnoteworthy to point out that heretofore no reference appears in theliterature about any possible use of delta opioid receptor agonists,either peptidic or non-peptidic, in treatment of premature ejaculation.

[0121] Definitions

[0122] Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular drugdelivery systems. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only, andis not intended to be limiting.

[0123] In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

[0124] The terms “active agent,” as used herein means a chemicalmaterial or compound which, when administered to an organism (human oranimal) induces a desired pharmacologic effect. Included are derivativesand analogs of those compounds or classes of compounds specificallymentioned which also induce the desired pharmacologic effect.

[0125] The terms “transurethral,” “intraurethral” and “urethral” tospecify the mode of administration as used herein are usedinterchangeably to refer to delivery of the drug into the urethra suchthat the drug contacts and passes through the wall of the urethra.

[0126] The term “intracavemosal” as used herein means another mode ofdrug administration and involves injection into one or both corpora ofthe corpora cavernosal tissues of the penis.

[0127] By the term “transdermal” delivery, applicants intend to includeboth transdermal (or “percutaneous”) and transmucosal administration,i.e., delivery by passage of a drug through the skin or mucosal tissueand into the bloodstream.

[0128] The term “topical administration” is used in its conventionalsense to mean delivery of a topical drug or pharmacologically activeagent to the skin or mucosa.

[0129] “Carriers” or “vehicles” as used herein means carrier materialssuitable for drug administration. Carriers and vehicles useful hereininclude any such materials known in the art, e.g., any liquid, gel,solvent, liquid diluent, solubilizer, or the like, which is nontoxic andwhich does not interact with other components of the composition in adeleterious manner.

[0130] By an “effective” amount of a drug or pharmacologically activeagent is meant a nontoxic but sufficient amount of the drug or agent toprovide the desired effect.

[0131] Active Agents for Treating Premature Ejaculation

[0132] In order to carry out the method of the invention, at lease onedelta opioid receptor agonist is administered to male subject with ahistory of premature ejaculation. In a first embodiment, suitable deltaopioid receptor agonists that can be administered to treat prematureejaculation include, but are not limited to;

[0133] deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH₂);

[0134] deltorphin II (Tyr-D-Ala-Phe-Glu-Val-Val-Gly-HH₂);

[0135] Biphalin;

[0136] DADLE [D-Ala 2, D-Leu⁵] enkephalin;

[0137] [D-Ser 2, Leu⁵]enkephalil-Thr;

[0138] [D-Pen,D-Pen⁵]-enkephalin;

[0139] compounds of the formulae:

[0140] (I)

[0141] wherein:

[0142] Ar¹ is a 5- or 6-member carbocyclic or heterocyclic aromatic ringwith atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur and may include thiophenyl, thiazolyl, furanyl,pyrrolyl, phenyl, or pyridyl, and having on a first carbon atom thereofa substituent Y and on a second ring carbon thereof a substituent R¹,

[0143] Y is selected from the group consisting of:

[0144] hydrogen;

[0145] halogen;

[0146] C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl;

[0147] C₁-C₆ haloalkyl;

[0148] C₁-C₆ alkoxy;

[0149] C₃-C₆ cycloalkoxy;

[0150] sulfides of the formula SR⁸ where R⁸ is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, arylalkyl having a C₅-C₁₀ arylmoiety and an C₁-C₆ alkyl moiety, or C₅-C₁₀aryl;

[0151] sulfoxides of the formula SOR⁸ where R⁸ is the same as above;

[0152] sulfones of the formula SO₂R⁸ where R⁸ is the same as above;

[0153] nitrile;

[0154] C₁-C₆ acyl;

[0155] alkoxycarbonylamino (carbamoyl) of the formula NHCO₂R₈ where R⁸is the same as above;

[0156] carboxylic acid, or an ester, amide, or salt thereof;

[0157] aminomethyl of the formula CH₂NR⁹R¹⁰ where R⁹ and R¹⁰ may be thesame or different, and may be hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₂-C₆ hydroxyalkyl, C₂-C₆ methoxyalkyl, C₃-C₆ cycloalkyl,or C₅-C₁₀ aryl, or R⁹ and R¹⁰ together may form a ring of 5 or 6 atoms,the ring atoms selected from the group consisting of N and C;

[0158] carboxamides of the formula CONR⁹ R¹⁰ where R⁹ and R¹⁰ are thesame as above, or C₂-C₃₀ peptide conjugates thereof; and

[0159] sulfonamides of the formula SO₂NR⁹R¹⁰ where R⁹ and R¹⁰ are thesame as above;

[0160] Z is selected from the group consisting of:

[0161] hydrogen, hydroxy and carboxy and esters thereof;

[0162] alkoxy, carboxyalkoxy, alkoxy-carboxylic acid, hydroxymethyl, andesters thereof; and

[0163] amino, carboxamides and sulfonamides thereof;

[0164] G is carbon or nitrogen;

[0165] R¹ is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl;

[0166] R² is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl;

[0167] R³, R⁴ and R⁵ may be the same or different, and are independentlyselected from hydrogen and methyl, and wherein at least one of R³, R⁴ orR⁵ is not hydrogen, subject to the proviso that the total number ofmethyl groups does not exceed two, or any two of R³, R⁴ and R⁵ togethermay form a bridge of 1 to 3 carbon atoms;

[0168] R⁶ is selected from the group consisting of:

[0169]  hydrogen;

[0170]  C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl;

[0171]  C₃-C₆ cycloalkyl;

[0172]  arylalkyl having C₅-C₁₀ aryl and C₁-C₆ alkyl moieties;

[0173]  alkoxyalkyl having C₁-C₄ alkoxy and C₁-C₄ alkyl moieties;

[0174]  C₂-C₄ cyanoalkyl;

[0175]  C₂-C₄ hydroxyalkyl;

[0176]  aminocarbonylalkyl having a C₁-C₄ alkyl moiety; and

[0177]  R¹²COR¹³, where R¹² is C₁-C₄ alkylene, and R¹³ is C₁-C₄ alkyl orC₁-C₄ alkoxy or hydroxy,

[0178] or R⁶ is

[0179] and Ar² is a 5 or 6-member carbocyclic or heterocyclic aromaticring with atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur, and having on a carbon atom thereof a substituent X,

[0180] wherein X is selected from the group consisting of a halogen(fluorine, bromine, chlorine, iodine), hydrogen, hydroxy, and estersthereof; carboxy and esters thereof; C1-C4 carboxyalkyl and estersthereof; alkoxy, alkyl carboxylic acid, carboxylic acid, hydroxymethyl,and esters thereof; and amino, and carboxamides and sulfonamidesthereof; and

[0181] R⁷ is hydrogen or fluorine;

[0182] (II)

[0183] wherein

[0184] R₁ and R₂, which can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, C₄₋₆cycloalkylalkyl, C₃₋₆ alkenyl, C₃₋₅ alkynyl, aryl, aralkyl or furan-2 or3-yl alkyl or may form together a C₃₋₇ alkyl ring which may beinterrupted by oxygen.

[0185] R₃ and R₄, which can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl, or R₄ is oxygen forming with the carbonatom to which is attached a C═O group;

[0186] R₅ is hydrogen, hydroxy, C₁₋₃ alkoxy, thiol or alkylthio;

[0187] R₆ is phenyl, halogen, NH₂ or a para or meta —C(Z)—R₈ group, inwhich Z is oxygen or sulphur;

[0188] R₈ is C₁₋₈-alkyl, C₁₋₈-alkoxy or NR₉R₁₀, wherein R₉ and R₁₀,which may be the same or different, are hydrogen, straight or branchedC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, aryl oraralkyl,

[0189] or R₆ is a para or meta

[0190]  group

[0191] in which R₁₁ and R₁₂ which may the same or different arehydrogen, straight or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆cycloalkylalkyl, C₃₋₆ alkenyl, aryl, aralkyl or an optionallysubstituted heterocyclic ring, and Z is as defined above; and,

[0192] R₇ is hydrogen, straight or branched C₁₋₈ alkyl or halogen;

[0193] (III)

[0194] wherein,

[0195] R₁ and R₂, can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, C₄₋₆cycloalkylalkyl, C₃₋₆ alkenyl, C₃₋₅ alkynyl, aryl, aralkyl or furan-2 or3-yl alkyl or may form together a C₃₋₇ alkyl ring which may beinterrupted by oxygen.

[0196] R₃ and R₄, can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl;

[0197] R₅ is hydroxy, C₁₋₆ alkoxy, thiol or alkylthio;

[0198] R₆ is a —C(Z)—R₈ group, wherein Z is oxygen or sulphur, R₈ isC₁₋₈-alkyl, C₁₋₈-alkoxy or NR₉R₁₀, wherein R₉ and R₁₀, which may be thesame or different, are hydrogen, straight or branched C1-6 alkyl, C₃₋₇cycloalkyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, aryl or aralkyl,

[0199] or R₆ is a meta or para

[0200]  group

[0201] wherein R₁₁ and R₁₂ have the same meaning as R₉ and R₁₀ ortogether form an optionally substituted heterocyclic ring and Z is asdefined above, and R₇ is hydrogen, straight or branched C₁₋₈ alkyl orhalogen; and

[0202] (IV)

[0203] wherein

[0204] A is N or C—X

[0205] wherein

[0206] X is H or C₁₋₄ alkyl;

[0207] G is C—Y

[0208] wherein

[0209] Y is H or C₁₋₄ alkyl;

[0210] B is an optional C₁₋₆ hydrocarbyl group, optionally substituted;

[0211] L is an optional C₁₋₆ hydrocarbyl group, optionally substituted;

[0212] and wherein A, B, and L in combination with the N constitute afirst ring structure which has from 5-7 atoms in the ring;

[0213] further wherein:

[0214] either D is H or a C₁₋₁₀ hydrocarbyl group,

[0215] or D is a C₁₋₁₀ hydrocarbyl group linked to B or L to form asecond ring structure which includes the N of the first ring structure,which second ring structure is fused to the first ring structure andwhich second ring structure has from 5-7 atoms in the ring;

[0216] E is a phenyl group substituted by at least one or more ofhydroxy, C₁₋₄ alkoxy, or NH₂SO₂ C₁₋₄ alkylene;

[0217] F represents a combination of a phenyl group and a heterocyclicgroup, wherein

[0218] (i) the phenyl group is positioned intermediate (in between) Gand the heterocyclic group;

[0219] (ii) the phenyl group is fused to the heterocyclic group or islinked directly to the heterocyclic group or is attached via a spacergroup to the heterocyclic group, wherein the spacer group is any one ofC₁₋₄ alkylene, carbonyl or SO₂; and

[0220] (iii) the heterocyclic group is substituted by at least one ormore of: a COOH group, a bio-isostere of a COOH group, a biolabile esterderivative of a COOH group, a C₁₋₁₀ hydrocarbyl group comprising one ormore COOH groups, a C₁₋₁₀ hydrocarbyl group comprising one or morebio-isosteres of a COOH group, or a C₁₋₁₀ hydrocarbyl group comprisingone or more biolabile ester derivatives of a COOH group;

[0221] and pharmaceutically acceptable esters and salts of the compounds(I)-(IV).

[0222] As used herein, in reference to the present invention, the term“alkyl” is intended to be broadly construed as encompassing: (i) alkylgroups of straight-chain as well as branched chain character; (ii)unsubstituted as well as substituted alkyl groups, wherein thesubstituents of substituted alkyl groups may include any stericallyacceptable substituents which are compatible with such alkyl groups andwhich do not preclude the efficacy of the diarylmethylpiperazine deltaopioid receptor agonist for its intended utility (examples ofsubstituents for substituted alkyl groups include halogen (e.g., fluoro,chloro, bromo, and iodo), amino, amido, C₁-C₄ alkyl, C₁-C₄ alkoxy,nitro, hydroxy, etc.); (iii) saturated alkyl groups as well asunsaturated alkyl groups, the latter including groups such asalkenyl-substituted alkyl groups (e.g., allyl, methallyl, propallyl,butenylmethyl, etc.), alkynyl-substituted alkyl groups, and any otheralkyl groups containing sterically acceptable unsaturation which iscompatible with such alkyl groups and which does not preclude theefficacy of the diarylmethylpiperazine delta opioid receptor agonist forits intended utility;

[0223] and (iv) alkyl groups including linking or bridge moieties, e.g.,heteroatoms such as nitrogen, oxygen, sulfur, etc.

[0224] As used herein, in reference to the present invention, the term“aryl” is intended to be broadly construed as referring to carbocyclic(e.g., phenyl, naphthyl) as well as heterocyclic aromatic groups (e.g.,pyridyl, thienyl, furanyl, etc.) and encompassing unsubstituted as wellas substituted aryl groups, wherein the substituents of substituted arylgroups may include any sterically acceptable substituents which arecompatible with such aryl groups and which do not preclude the efficacyof the diarylmethylpiperazine delta opioid receptor agonist for itsintended utility. Examples of substituents for substituted aryl groupsinclude hydrogen, one or more of halogen (e.g., fluoro, chloro, bromo,and iodo), amino, amido, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro,trifluoromethyl, hydroxy, hydroxyalkyl containing a C₁-C₄ alkyl moiety,etc.

[0225] The active agent may be administered in the form of apharmaceutically acceptable salt, ester, amide or prodrug or combinationthereof. Salts, esters, amides and prodrugs of the active agents may beprepared using standard procedures known to those skilled in the art ofsynthetic organic chemistry and described, for example, by J. March,Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed.(New York: Wiley-Interscience, 1992). For example, acid addition saltsare prepared from the free base (typically wherein the neutral form ofthe drug has a neutral —NH₂ group) using conventional means, involvingreaction with a suitable acid. Generally, the base form of the activeagent is dissolved in a polar organic solvent such as methanol orethanol and the acid is added thereto. The resulting salt eitherprecipitates or may be brought out of solution by addition of a lesspolar solvent. Suitable acids for preparing acid addition salts includeboth organic acids, e.g., acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like, as well asinorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like. An acid addition saltmay be reconverted to the free base by treatment with a suitable base.Conversely, preparation of basic salts of acid moieties which may bepresent on an active agent are prepared in a similar manner using apharmaceutically acceptable base such as sodium hydroxide, potassiumhydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or thelike.

[0226] Examples of pharmaceutically acceptable salts include saltsderived from an appropriate base, such as an alkali metal (for example,sodium, potassium), an alkaline earth metal (for example, calcium,magnesium), ammonium and NR′⁴ ⁺ (wherein R′ is C₁-C₄ alkyl).Pharmaceutically acceptable salts of an amino group include salts of:organic carboxylic acids such as acetic, lactic, tartaric, malic,lactobionic, fumaric, and succinic acids; organic sulfonic acids such asmethanesulfonic, ethanesulfonic, isethionic, benzenesulfonic andp-toluenesulfonic acids; and inorganic acids such as hydrochloric,hydrobromic, sulfuric, phosphoric and sulfamic acids. Pharmaceuticallyacceptable salts of a compound having a hydroxyl group consist of theanion of said compound in combination with a suitable cation such asNa⁺, NH₄ ^(+, or NR′) ₄ ⁺ (wherein R′ is for example a C₁₋₄ alkylgroup).

[0227] Preparation of esters involves functionalization of hydroxyland/or carboxyl groups that may be present within the molecularstructure of the drug. The esters of hydroxyl groups are typicallyacyl-substituted derivatives of free alcohol groups, i.e., moietieswhich are derived from carboxylic acids of the formula RCOOH where R isalkyl, and preferably is lower alkyl. Esters can be reconverted to thefree acids, if desired, by using conventional hydrolysis procedures.Examples of pharmaceutically acceptable esters include carboxylic acidesters of the hydroxyl group in the compounds of the present inventionin which the non-carbonyl moiety of the carboxylic acid portion of theester grouping is selected from straight or branched chain alkyl (e.g.n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g. methoxymethyl), arylalkyl(e.g. benzyl), aryloxyalky (e.g. phenoxymethyl), and aryl (e.g. phenyl);alkyl-, aryl-, or arylalkylsulfonyl (e.g. methanesulfonyl); amino acidesters (e.g. L-valyl or L-isoleucyl); dicarboxylic acid esters (e.g.hemisuccinate); carbonate esters (e.g. ethoxycarbonyl); carbamate esters(e.g. dimethylaminocarbonyl, (2-aminoethyl)aminocarbonyl); and inorganicesters (e.g. mono-, di- or triphosphate). The esters of carboxyl groupswithin the molecular structure of the drug are typically prepared fromC₁-C₄ alcohols (e.g., ethanol, propanol) or arylalkyl alcohols (e.g.,benzyl alcohols). Preparation of amides and prodrugs can be carried outin an analogous manner.

[0228] Other derivatives and analogs of the active agents may beprepared using standard techniques known to those skilled in the art ofsynthetic organic chemistry, or may be deduced by reference to thepertinent literature. In addition, chiral active agents may be inisomerically pure form, or they may be administered as a racemic mixtureof isomers.

[0229] Pharmaceutical Formulations and Modes of Administration:

[0230] Depending on the intended mode of administration, thepharmaceutical compositions may be in the form of solid, semi-solid orliquid dosage forms, such as, for example, tablets, suppositories,pills, capsules, powders, liquids, suspensions, creams, ointments,lotions or the like, preferably in unit dosage form suitable for singleadministration of a precise dosage. The compositions include aneffective amount of the delta opioid receptor agonist in combinationwith a pharmaceutically acceptable carrier, if desired, and, inaddition, may include other pharmaceutical agents, adjuvants, diluents,buffers, etc. The amount of active agent administered will, of course,be dependent on the subject being treated, the subject's weight, themanner of administration and the judgment of the prescribing physician.

[0231] For solid compositions, conventional nontoxic solid carriersinclude, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose,sucrose, magnesium carbonate, and the like. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, etc., an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate,etc. Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: theScience and Practice of Pharmacy, 19^(th) Ed. (Easton, Pa.: MackPublishing Co., 1995).

[0232] For oral administration, the composition will generally take theform of a tablet or capsule, or may be an aqueous or nonaqueoussolution, suspension or syrup. Tablets and capsules are preferred oraladministration forms. Tablets and capsules for oral use will generallyinclude one or more commonly used carriers such as lactose andcornstarch. Lubricating agents, such as magnesium stearate, are alsotypically added. When liquid suspensions are used, the active agent maybe combined with emulsifying and suspending agents. If desired,flavoring, coloring and/or sweetening agents may be added as well. Otheroptional components for incorporation into an oral formulation hereininclude, but are not limited to, preservatives, suspending agents,thickening agents, and the like.

[0233] Parenteral administration, if used, is generally characterized byinjection. Injectable formulations can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solubilization or suspension in liquid prior to injection, or asemulsions. Preferably, sterile injectable suspensions are formulatedaccording to techniques known in the art using suitable carriers,dispersing or wetting agents and suspending agents. The sterileinjectable formulation may also be a sterile injectable solution or asuspension in a nontoxic parenterally acceptable diluent or solvent.Among the acceptable vehicles and solvents that may be employed arewater, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils, fatty esters or polyols areconventionally employed as solvents or suspending media. A more recentlyrevised approach for parenteral administration involves use of a slowrelease or sustained release system, such that a constant level ofdosage is maintained.

[0234] Intracavernosal injection can be carried out by use of a syringeany other suitable device. The injection is made on the dorsum of thepenis by placement of the needle to the side of each dorsal vein andinserting it deep into the corpora.

[0235] The active agent can be administered in a pharmaceuticalformulation suitable for transurethral drug delivery. The formulationcontains one or more selected carriers or excipients, such as water,silicone, waxes, petroleum jelly, polyethylene glycol (“PEG”), propyleneglycol (“PG”), liposomes, sugars such as mannitol and lactose, and/or avariety of other materials, with polyethylene glycol and derivativesthereof particularly preferred.

[0236] Depending on the delta opioid receptor agonist administered, itmay be desirable to incorporate a transurethral permeation enhancer inthe urethral dosage form. Examples of suitable transurethral permeationenhancers include dimethylsulfoxide (“DMSO”), dimethyl formamide(“DMF”), N,N-dimethylacetamide (“DMA”), decylmethylsulfoxide (“C₁₀MSO”), polyethylene glycol monolaurate (“PEGML”), glycerol monolaurate,lecithin, the 1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (available under the trademarkAzone.RTM. from Nelson Research & Development Co., Irvine, Calif.),SEPA.RTM. (available from Macrochem Co., Lexington, Mass.), alcohols(e.g., ethanol), detergents (such as Tergitol.RTM., Nonoxynol-9.RTM. andTWEEN-80.RTM.) and the like.

[0237] Transurethral formulations may additionally include one or moreenzyme inhibitors effective to inhibit drug-degrading enzymes that maybe present in the urethra. Such enzyme inhibiting compounds may bedetermined by those skilled in the art by reference to the pertinentliterature and/or using routine experimental methods. Additionaloptional components include excipients, preservatives (e.g.,antioxidants), chelating agents, solubilizing agents (e.g.,surfactants), and the like, as will be appreciated by those skilled inthe art of drug formulation preparation and delivery.

[0238] Transurethral drug administration can be carried out in a numberof different ways using a variety of urethral dosage forms. For example,the composition can be introduced into the urethra from a flexible tube,squeeze bottle, pump or aerosol spray. The active agents may also becontained in coatings, pellets or suppositories that are absorbed,melted or bioeroded in the urethra. Urethral suppository formulationscontaining PEG or a PEG derivative amay be used and may be formulatedusing conventional techniques, e.g., compression molding heat molding orthe like, as will be appreciated by those skilled in the art and asdescribed in the pertinent literature and pharmaceutical texts. See, forexample, Remington, referenced above. The PEG or PEG derivativepreferably has a molecular weight M_(w) in the range of about 200 to2500. Suitable polyethylene glycol derivatives include polyethyleneglycol fatty acid esters, for example, polyethylene glycol monostearate,polyethylene glycol sorbitan esters, e.g., polysorbates, and the like.It is also preferred that urethral suppositories contain one or moresolubilizing agents effective to increase the solubility of the activeagent in the PEG or other transurethral vehicle. The solubilizing agentmay be a nonionic, anionic, cationic or amphoteric surfactant.

[0239] It may be desirable to deliver the active agent in a urethraldosage form, which provides for controlled or sustained release of theactive agent. In such a case, the dosage form typically comprises abiocompatible, biodegradable material, typically a biodegradablepolymer. Examples of such polymers include polyester,polyalkylcyanoacrylate, polyorthoester, polyanhydride, albumin, gelatinand starch. These and other polymers can be used to providebiodegradable microparticles that enable controlled and sustained drugrelease, which in turn will minimize the required dosing frequency.

[0240] The compounds of the invention may also be delivered through theskin or muscosal tissue using conventional transdermal drug deliverysystems, i.e., transdermal “patches” wherein the agent is typicallycontained within a laminated structure that serves as a drug deliverydevice to be affixed to the body surface. In such a structure, thepharmaceutical composition is typically contained in a layer, or“reservoir,” underlying an upper backing layer. The laminated device maycontain a single reservoir, or it may contain multiple reservoirs. Inone embodiment, the reservoir comprises a polymeric matrix of apharmaceutically acceptable contact adhesive material that serves toaffix the system to the skin during drug delivery. Examples of suitableskin contact adhesive materials include, but are not limited to,polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates,polyurethanes, and the like. Alternatively, the active agent-containingreservoir and skin contact adhesive are present as separate and distinctlayers, with the adhesive underlying the reservoir which, in this case,may be either a polymeric matrix as described above, or it may be aliquid or gel reservoir, or may take some other form. The backing layerin these laminates, which serves as the upper surface of the device,functions as the primary structural element of the laminated structureand provides the device with much of its flexibility. The materialselected for the backing layer should be substantially impermeable tothe active agent and any other materials that are present.

[0241] Alternatively, the pharmaceutical compositions of the inventionmay be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable nonirritating excipient which is solid at room temperature butliquid at the rectal temperature and therefore will melt in the rectumto release the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols. The suppository will preferably, although notnecessarily, be on the order of 2 to 20 mm, preferably 5 to 10 mm inlength and less than about 5 mm, preferably less than about 2 mm inwidth. The weight of the suppository form will typically be in the rangeof approximately 1 mg to 50 mg. However, it will be appreciated by thoseskilled in the art that the size of the suppository can and will vary,depending on the potency of the active agent, the nature of thecomposition, and other factors.

[0242] The pharmaceutical compositions of the invention may also beadministered by nasal aerosol or inhalation. Nasal spray formulationscomprise purified aqueous solutions of the active compounds withpreservative agents and isotonic agents. Such formulations arepreferably adjusted to a pH and isotonic state compatible with the nasalmucous membranes. Such compositions are prepared according to techniqueswell-known in the art of pharmaceutical formulation and may be preparedas solutions in saline, employing benzyl alcohol or other suitablepreservatives, absorption promoters to enhance bioavailability,propellants such as fluorocarbons or nitrogen, and/or other conventionalsolubilizing or dispersing agents.

[0243] The delta opioid receptor agonists of the present invention maybe included in formulations for topical drug delivery, such as inointments and creams. Ointments are semisolid preparations that aretypically based on petrolatum or other petroleum derivatives. Creamscontaining the selected active agent, are, as known in the art, viscousliquid or semisolid emulsions, either oil-in-water or water-in-oil.Cream bases are water-washable, and contain an oil phase, an emulsifierand an aqueous phase. The oil phase, also sometimes called the“internal” phase, is generally comprised of petrolatum and a fattyalcohol such as cetyl or stearyl alcohol; the aqueous phase usually,although not necessarily, exceeds the oil phase in volume, and generallycontains a humectant. The emulsifier in a cream formulation is generallya nonionic, anionic, cationic or amphoteric surfactant. The specificointment or cream base to be used, as will be appreciated by thoseskilled in the art, is one that will provide for optimum delivery of theactive agent. As with other carriers or vehicles, an ointment baseshould be inert, stable, nonirritating and nonsensitizing.

[0244] In some applications, it may be advantageous to utilize theactive agent in a “vectorized” form, such as by encapsulation of theactive agent in a liposome or other encapsulant medium, or by fixationof the active agent, e.g., by covalent bonding, chelation, orassociative coordination, on a suitable biomolecule, such as thoseselected from proteins, lipoproteins, glycoproteins, andpolysaccharides.

[0245] Ophthalmic formulations are prepared by a similar method to thenasal spray, except that the pH and isotonic factors are preferablyadjusted to match that of the eye.

[0246] The pharmaceutical formulations discussed above may furthercontain one or more pharmacologically active agents in addition to thedelta opioid receptor agonists, such as vasodilators.

[0247] The compounds contemplated by the invention include those setforth above, as well as physiologically functional derivatives thereof.By “physiologically functional derivative” is meant a pharmaceuticallyacceptable salt, ether, ester or salt of an ether or ester of thecompounds set forth above or any other compound which, uponadministration to the recipient, is capable of providing (directly orindirectly) the said compound or an active metabolite or residuethereof.

[0248] The amount of delta opioid receptor agonist administered, and thedosing regimen used, will, of course, be dependent on the particulardelta opioid receptor agonist selected, the age and general condition ofthe subject being treated, the severity of the subject's condition, andthe judgment of the prescribing physician. Generally, the daily dosagewhen administered locally will be less than the dosage normally given inconjunction with systemic modes of administration, and typically, thedelta agonist will be administered one to four times daily or, with someactive agents, just prior to intercourse. Alternatively, a large initialloading dose can be used to achieve effective levels of the active agentand can be followed by smaller doses to maintain those levels. A typicaldaily dose of an active agent as administered locally is generally inthe range of approximately 0.1 to 100 mg/kg body weight of therecipient. Depending on the half-life of the delta opioid receptoragonist and the availability via the chosen route of administration, thedosing regimen can be modulated in order to achieve satisfactory controlof the onset of ejaculation.

[0249] In general, while the effective dosage of compounds of theinvention for therapeutic use may be widely varied in the broad practiceof the invention, depending on the specific condition involved, asreadily determinable within the skill of the art, suitable therapeuticdoses of the compounds of the invention, for each of the appertainingcompositions described herein, and for achievement of therapeuticbenefit in treatment of each of the conditions described herein, willpreferably in the range of 10 micrograms (μg) to 500 milligrams (mg) perkilogram body weight of the recipient per day, more preferably in therange of 50 μg to 75 mg per kilogram body weight per day, and mostpreferably in the range of 1 mg to 50 mg per kilogram body weight perday. The desired dose is may be presented as two, three, four, five,six, or more sub-doses administered at appropriate intervals throughoutthe day.

[0250] The mode of administration and dosage forms will of course affectthe therapeutic amounts of the compounds which are desirable andefficacious for the given treatment application. For example, orallyadministered dosages typically are at least twice, e.g., 2-10 times, thedosage levels used in parenteral administration methods, for the sameactive ingredient. In oral administration, dosage levels for compoundsof the present invention may be on the order of 5-200 mg/70 kg bodyweight/day. In tablet dosage forms, typical active agent dose levels areon the order of 10-100 mg per tablet.

[0251] Kits

[0252] The invention also encompasses a kit for patients to carry outthe present method of treating premature ejaculation. The kit containsthe pharmaceutical composition to be administered, a device foradministering the pharmaceutical composition (e.g., a transurethral drugdelivery device such as a syringe, a transdermal patch), a container,preferably sealed, for housing the active agent and delivery deviceduring storage and prior to use, and instructions for carrying out drugadministration in an effective manner. The formulation may consist ofthe delta opioid receptor agonist in unit dosage form. The kit maycontain multiple formulations of different dosages of the same agent.The instructions may be in written or pictograph form, or can be onrecorded media including audio tape, video tape, or the like.

[0253] It is to be understood that while the invention has beendescribed in conjunction with the preferred specific embodimentsthereof, that the foregoing description as well as the examples whichfollow are intended to illustrate and not limit the scope of theinvention. Other aspects, advantages and modifications within the scopeof the invention will be apparent to those skilled in the art to whichthe invention pertains.

[0254] The following examples are illustrative of synthetic proceduresthat may be advantageously utilized to make compounds of the presentinvention.

[0255] Melting points were determined with a Thomas-Hoover apparatus andare uncorrected. All chemical reagents were purchased from AldrichChemical Company, Milwaukee, Wis., unless otherwise specified.Commercial solvents were used without further purification. NMR spectrawere obtained on a variety of instruments ranging from 200 to 600 MHz infield strength. HPLC analyses were performed with a Waters liquidchromatography system equipped with a 700 Satellite WISP, 600E SystemController and a 991 Photodiode Array. Analytical gas chromatography wasperformed on a Hewlett-Packard Series II instrument, Model 5890 withflame ionization detector using helium as the carrier gas (injectortemperature, 225° C.; detector temperature, 250° C.). Mass spectra wereperformed by various contractual sources using chemical ionization (CI),electrospray (ES), or fast-atom bombardment (FAB) instrumentation.Optical rotations were obtained with a Perkin-Elmer 241 polarimeter.Analytical thin layer chromatography was performed on E. Merck glassplates pre-coated with silica gel GF (250 microns). Elemental analyseswere performed by Atlantic Microlab, Norcross, Ga.

EXAMPLE 1

[0256]4-((alpha-S)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide

[0257] 4-Carboxybenzaldehyde (150 g, 100 mmol) was added to a 250 mL,3-necked round bottom flask and stirred under nitrogen in 110 mL oftoluene. Thionyl chloride (8.75 mL, 120 mmol) was added to the mixture,followed by the addition of 6 drops of DMF. A reflux condenser fittedwith a calcium chloride drying tube was placed on the flask. Thereaction was placed in an oil bath and heated at a bath temperaturemaintained below 120° C. The mixture was allowed to reflux for 1 hourafter a clear solution was obtained and then cooled to room temperature.The solution was diluted with anhydrous toluene, and all volatiles wereremoved under vacuum.

[0258] The crude acid chloride was dissolved in 200 mL of drytetrahydrofuran and cooled in an ice/water bath. Diethylamine (31.35 mL,300 mmol) in 70 mL of dry tetrahydrofuran was added dropwise via anaddition funnel. The cloudy solution was allowed to warm to roomtemperature over 1 hour and stirred overnight. Water was added and theproduct was extracted with dichloromethane. The organic layer was washedwith water and saturated sodium chloride solution, dried over sodiumsulfate, and the solvent was removed under vacuum.3-Formyl-N,N-diethylbenzamide (17.72 g) was obtained as a light goldenoil (86% unchromatographed yield). ¹H NMR (300 MHz, DMSO-d₆): δ1.04-1.18 (m, 6H); 3.17-3.45 (m, 4H); 7.65-7.66 (m, 2H); 7.85 (s, 1H);7.93-7.94 (m, 1H); 10.03 (s, 1H).

[0259] A 12 L, 3-necked round bottom flask was charged withtrans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had beenrecrystallized from toluene to mp=115-119° C., and 600 mL of water. Theflask was cooled in an ice bath and a solution of methanesulfonic acid(1290 g, 13.4 mol) in 600 mL of water was added slowly with stirring andcooling to maintain the temperature below 40° C. The solution was cooledto 20° C. and 800 mL of ethanol was added. A 500 mL addition funnel wasfilled with 60% aqueous potassium acetate from a 2 L reservoir of thesolution, and potassium acetate was added to the reaction flask toadjust the pH to 4.0. A second addition funnel was charged with asolution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL oftetrahydrofuran. The ethyl chloroformate and potassium acetate solutionswere simultaneously added dropwise with adjustment of rate to maintainthe reaction solution at pH 4.0±0.1, with cooling as necessary tomaintain temperature at 25° C. After addition of the ethyl chloroformatewas complete, the reaction was stirred for 1 hour with continuedaddition of potassium acetate solution to maintain a pH of 4.0. Theorganic solvents were removed by distillation under vacuum. Theremaining aqueous solution was washed with 1500 mL of ethyl acetate toremove any bis-carbamate impurity. The ethyl acetate wash was extractedwith two 500 mL portions of 1M hydrochloric acid to recover desiredproduct. The acid extracts were combined with the original aqueoussolution and the pH was adjusted to 11 by addition of 10M sodiumhydroxide, with cooling to maintain temperature below 40 C. The aqueoussolution was extracted with two 1500 mL portions of ethyl acetate, thecombined extracts were dried over magnesium sulfate, and the solvent wasremoved to give 927 g (74%) ethyltrans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.

[0260] A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate(643 g, 3.45 mol), allyl bromide (328 mL, 3.80 mol), and sodiumcarbonate (440 g, 4.15 mol) in 2500 mL of acetonitrile was heated atreflux for 1.5 hours. The reaction was cooled to room temperature,filtered, and the solvent removed under vacuum. The residue wasdissolved in 4000 mL of dichloromethane and washed with two 500 mLportions of 1 M sodium hydroxide. The dichloromethane solution was driedover magnesium sulfate and the solvent was removed to give 630 g (81%)of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.

[0261] Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g,2.78 mol) was added to a solution of 87% potassium hydroxide pellets(2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5hours. Carbon dioxide evolution was observed for the first 0.5-1 hour ofheating. The reaction was cooled below reflux temperature and 2000 mL oftoluene was carefully added. Ethanol was removed by azeotropicdistillation at 105° C., while adding an additional 4000 mL of tolueneto the reaction flask during the course of the distillation. Aftercollection of 9000 mL of distillate, the reaction was cooled to 100° C.and 1000 mL of toluene was carefully added. The solution was slowlycooled to 5° C. and maintained at 5 C for 30 minutes. The solution wasfiltered, and the filter cake was washed with an additional 1500 mL oftoluene. The filtrate was washed with 1000 mL of water, dried overmagnesium sulfate, and the solvent was removed to give 296 g (69%) oftrans-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz,DMSO-d₆): δ 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t,J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33(dd, J₁=5 Hz, J₂=14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz,1H) 5.8 (m, 1H).

[0262] Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., SouthPlainfield, N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot (˜60 C) 95%ethanol (16 L) and racemic trans-1-allyl-2,5-dimethylpiperazine (500 g,3.2 mol) was added in several portions (caution: exothermic).

[0263] The hot solution was seeded with crystals of thediastereoisomerically pure salt (obtained from a previous small-scaleresolution) and cooled to room temperature over 2-3 hours. The solutionwas slowly stirred for 2 days at room temperature. The resulting saltwas collected by filtration, washed twice with 95% ethanol, and driedunder vacuum to give 826.5 g of a white solid (47%). The process wasrepeated with a second batch of the di-p-toluoyl-D-tartaric acid andracemic trans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).

[0264] The total of 1695 g of salt was divided into three batches andeach batch was recrystallized twice in the following fashion. The saltwas dissolved in refluxing 95% ethanol (˜2.7 L/100 g of salt), andapproximately half of the ethanol was removed by distillation. (Note:vigorous stirring was necessary during distillation to preventcrystallization on the vessel wall.) The hot solution was seeded withcrystals of the pure diastereomeric salt, cooled to room temperature,and stirred slowly for 2 days before collecting the salt by filtration.(Note: a subsequent experiment suggested that crystallization time canbe reduced from 2 days to 8 hours.) The total amount recovered was 1151g. The salt was dissolved in 3 L of 2 M aqueous sodium hydroxide, andthe aqueous solution was extracted with four IL portions ofdichloromethane. The organic extracts were combined, dried over sodiumsulfate, and solvent removed by rotary evaporation (temperature <20° C.)to give 293 g (29% based on racemic weight) of(2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil. [α]_(D) ²⁰=−55.1(abs. ethanol, c=1.2). The trifluoroacetamide of the product wasprepared with trifluoroacetic anhydride and analyzed by chiral capillarygas chromatography (Chiraldex B-PH column, 20 m×0.32 mm, AdvancedSeparation Technologies Inc., Whippany, N.J., 120° C.) indicating anenantiopurity of >99% ee (retention time of desired enantiomer, 11.7min; other enantiomer, 10.7 min).

[0265] A solution of 4-formyl-N,N-diethylbenzamide (4.105 g, 20 mmol),benzotriazole (2.38 g, 20 mmol) and (2R,5S)-1-allyl-2,5-dimethylpiperazine (3.085 g, 20 mmol) in toluene (200mL) was heated under reflux with azeotropic removal of water for 2.5 h.The volume of the reaction mixture was reduced to approximately 75 mL bydistillation. Anhydrous tetrahydrofuran (50 mL) was added to thesolution under nitrogen, and the reaction was stirred during theaddition of phenylmagnesium bromide (1.0 M in tetrahydrofuran, 40 mL, 40mmol). The reddish brown suspension was stirred at ambient temperaturefor 1 h and quenched with saturated aqueous ammonium chloride solution(10 mL). The yellow suspension was stirred for 15 min, and anhydrousmagnesium sulfate (10 g) added. The suspension was stirred for a further15 min and filtered. The filter cake was washed with tetrahydrofuran,and the combined filtrate and washings were evaporated to a thick oil.The residue was partitioned between ethyl acetate (400 mL) and aqueoussodium hydroxide solution (1.0 M, 100 mL). The organic layer wasseparated and washed successively with 1M-NaOH (3×100 mL), water (100mL) and saturated aqueous sodium chloride solution (100 mL). The ethylacetate solution was extracted with 1.0 M HCl (2×25 mL), and thecombined acid extracts were basified to pH 10 with 10 M aqueous NaOH.The oily aqueous suspension was extracted with methylene chloride (2×25mL) and the organic layer dried over anhydrous magnesium sulfate. Themethylene chloride solution was evaporated to dryness, and thesemi-crystalline residue crystallized from ethyl acetate to yield thetitle compound (1.84 g, 21.9%). Calc. for C₂₇H₃₇N₃O 0.15H₂° C., 76.79;H, 8.90; N, 9.95. Found C, 76.79; H, 8.85; N, 9.87% ¹H NMR ((CD₃)₂SO,500 MHz); δ 0.94 (d, J=6.2 Hz, 3H); 1.09 (d, J=6.2 Hz, 3H, partiallyobscured by br m, 6H); 1.80 (m, 1H); 2.09 (dd, J=11, 7 Hz, 1H); 2.50 (brm, 1H, partially obscured by DMSO); 2.72 (dd, J=11, 2.8 Hz, 1H); 2.84(dd, J=14, 7 Hz, 1H); 3.16 (dd, J=14, 5.2 Hz, 1H); 3.28 (br m, 3H); 5.10(s, 1H), overlapped by 5.09 (d, J=10.6 Hz, 1H); 5.16 (dd, J=17, 1.4 Hz,1H); 5.79 (m, 1H); 7.28 (m, 5H); 7.38 (m, 2H); 7.42 (d, J=8 Hz, 2H).

EXAMPLE 2

[0266]4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide

[0267] The compound of Example 1 was de-allylated by the method of Genet[J. P. Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36,1267-1270 (1995)] as follows. A solution of4-((alpha-S)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide(Example 1, 8.392 g, 20 mmol) and thiosalicylic acid (3.70 g, 24 mmol)in anhydrous tetrahydrofuran (50 mL) was stirred under nitrogen for 3 hat room temperature with a catalyst solution prepared by dissolution ofbis(dibenzylidineacetone)palladium (575 mg, 1.0 mmol) and1,4-bis(diphenylphosphino)butane (426 mg, 1.0 mmol) in tetrahydrofuran(10 mL). The reaction mixture was evaporated to dryness, the residuedissolved in a mixture of ethyl acetate/ether (1:3, 300 mL) andextracted with 5% sodium carbonate solution (2×300 mL). The organiclayer was diluted with two volumes of pentane and extracted with3M-hydrochloric acid (6×50 mL). The aqueous solution was filtered toremove suspended solid and the pH adjusted to 12 with 5-M NaOH. Theresulting oily suspension was extracted with methylene chloride (2×125mL) and the combined organic extracts dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was crystallized fromethyl acetate to yield fine white needles of4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide(3.46 g). The product showed a single spot on thin layer chromatography(silica gel, EM60F₂₆₄, 4% NH₄OH/10% EtOH in ethyl acetate, R_(f)=0.47).¹H NMR (CDCl₃, 600 MHz); δ 0.93 (d, J=6.3 Hz, 3H); 1.12 (br m, 3H); 1.20(d, J=6.1 Hz, 3H); 1.24 (br m, 3H); 1.55 (dd, J=9.7, 11.3 Hz, 1H,partially obscured by br m, 2H); 2.33 (m, 1H); 2.68 (m,2H); 2.89 (m,1H); 2.92 (dd, J=12.1, 3.1 Hz, 1H); 3.29 (br m, 2H); 3.54 (br m, 2H);5.38 (s, 1H); 7.14 (m, 2H); 7.30 (m, 3H); 7.35 (m, 2H); 7.46 (d, J=7.8Hz, 2H).

EXAMPLE 3

[0268]4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide

[0269] A solution of4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide(1.898 g, 5.0 mmol) in 25 mL acetonitrile was added to sodium iodide (75mg, 0.5 mmol) and stirred during the addition of triethylamine (2.5 mL,1.815 g, 17.94 mmol), followed by 3-fluorobenzyl bromide (1.227 mL, 1.89g, 10.0 mmol). An immediate turbidity was observed on addition of the3-fluorobenzyl bromide, thickening to a copious white precipitate overone hour. The flask was sealed under nitrogen and the suspension stirredovernight at room temperature. The reaction mixture was evaporated todryness and and the residue was partitioned between ethyl acetate (40mL) and saturated sodium bicarbonate solution (10 mL). The supernatantorganic layer was separated and the aqueous layer extracted further withethyl acetate (2×40 mL). The combined organic extracts were dried overanhydrous sodium sulfate and evaporated to a pale yellow solid which wasdissolved in ethyl acetate (˜7.5 mL) and applied to an intermediate(4×15 cm) Biotage silica column. Elution with ethyl acetate gavefractions containing the product, as evidenced by t.l.c. (silica,EM60F₂₅₄, 100% EtOAc, Rf=0.78) were evaporated to dryness and dried atroom temperature and 2 mm Hg to yield the title compound as whitecrystals (2.372 g, 97.3%). Calc. for C₃₁H₃₈FN₃O: C, 76.35; H, 7.85; N,8.62; F, 3.90. Found C, 76.32; H, 7.89; N, 8.51; F, 3.90% ¹H NMR (CDCl₃,300 MHz); δ 1.06 (d, J=6.1 Hz, 3H); 1.15 (d, J=6.1 Hz, 3H, partiallyoverlapped by br m, 3H); 1.22 (br m, 3H); 1.94 (dd, J=10.8, 8.1 Hz, 1H);2.02 (dd, J=10.7, 8.2 Hz, 1H); 2.57 (br m, 2H); 2.67 (m, 2H); 3.18 (d,J=13.8 Hz, 1H); 3.28 (br m, 2H); 3.53 (br m, 2H); 3.87 (d, J=13.5 Hz,1H); 5.15 (s, 1H); 6.90 (br t, J=8.2 Hz, 1H); 7.04 (m, 2H); 7.21 (m,3H); 7.30 (m, 5H); 7.46 (d, J=8.0 Hz, 2H).

[0270] Also prepared from4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide(Example 2) by an essentially similar procedure to Example 3 were:

EXAMPLE 4

[0271]4-((alpha-S)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide

[0272] (71.8%). Calc. for C₃₁H₃₉N₃O: C, 79.28; H, 8.37; N, 8.95. FoundC, 79.05; H, 8.34; N, 8.91% ¹H NMR (CDCl₃, 500 MHz); δ 1.09 (d, J=6.2Hz, 3H); 1.12 (d, J=6.1 Hz, 3H); both doublets partially overlapped bybr m, 3H); 1.24 (br m, 3H); 1.72 (m, 1H); 1.93 (m, 1H); 2.02 (dd, J=9.3,8.4 Hz, 1H); 2.55 (m, 2H); 2.66 (dd, J=11.1, 2.4 Hz, 1H); 2.70 (dd,J=11, 2.5 Hz, 1H); 3.18 (d, J=13.8 Hz, 1H); 3.28 (br m, 2H); 3.55 (br m,2H); 3.92 (d, J=13.1 Hz, 1H); 5.18 (s, 1H); 7.20 (d, J=7.4 Hz, 2H,partially overlapped by m, 1H); 7.30 (m, 9H); 7.47 (d, J=8 Hz, 2H).

EXAMPLE 5

[0273]4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide

[0274] (68.9%). Calc. for C₃₁H₃₈FN₃O: C, 76.35; H, 7.85; N, 8.62; F,3.90. Found C, 76.35; H, 8.02; N, 8.60; F, 3.81% ¹H NMR (CDCl₃, 600MHz); δ 1.09 (d, J=6.1 Hz, 3H); 1.13 (d, J=6.1 Hz, 3H); (both doubletsoverlapped by br m, 3H); 1.24 (br m, 3H); 1.90 (br t, J=10.4 Hz, 1H);2.08 (dd, J=10.9, 8.6 Hz, 1H); 2.56 (br m, 2H); 2.66 (dd, J=11.5, 2.7Hz, 1H); 2.73 (dd, J=11.1, 2.4 Hz, 1H); 3.28 (br m, 2H); 3.34 (d, J=13.8Hz, 1H); 3.54 (br m, 2H); 3.88 (d, J=13.8 Hz, 1H); 5.19 (s, 1H); 7.00(br t, J=9.1 Hz, 1H); 7.07 (t, J=7.5 Hz, 1H); 7.19 (m, 3H); 7.29 (m,5H); 7.37 (br t, J=7.1 Hz, 1H); 7.46 (d, J=8.12H).

EXAMPLE 6

[0275]4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-pyridylmethyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide

[0276] (69.7%). Calc. for C₃₀H₃₈N₄O 0.15H₂O: C, 76.12; H, 8.16; N,11.84. Found C, 76.14; H, 8.36; N, 11.70%. ¹H NMR (CDCl₃, 600 MHz); δ1.05 (d, J=6.1 Hz, 3H); 1.11 (d, J=6.2 Hz, 3H; overlapped by br m, 3H);1.24 (br m, 3H); 1.96 (br t, J=10.0 Hz, 1H); 2.08 (dd, J=7.8, 4.1 Hz,1H); 2.59 (br d, J=4.9 Hz, 2H); 2.68 (m, 2H); 3.21 (d, J=14.0 Hz, 1H);3.27 (br m, 2H); 3.54 (br m, 2H); 3.86 (d, J=14.2 Hz, 1H); 5.13 (s, 1H);7.23 (d, J=7.4 Hz, 2H); 7.24 (d, J=5.6 Hz, 2H); 7.29 (d, J=8.2 Hz, 2H,partially obscuring doublet, 1H); 7.34 (br t, J=7.4 Hz, 2H); 7.46 (d,J=8.12H); 8.49 (d, J=5.9 Hz, 2H).

EXAMPLE 7

[0277]4-((alpha-S)-alpha-((2S,5R)-4-(3-Chlorobenzyl)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide

[0278] (75.8%). Calc. for C₃₁H₃₈ClN₃O: C, 73.86; H, 7.60; N, 8.34; Cl,7.03. Found C, 73.86; H, 7.68; N, 8.37; Cl, 7.01% ¹H NMR (CDCl₃, 600MHz); δ 1.06 (d, J=6.2 Hz, 3H); 1.12 (d, J=6.1 Hz, 3H, overlapping br m,3H); 1.23 (br m, 3H); 1.94 (br t, J=9.5 Hz, 1H); 2.01 (dd, J=11.1, 8.2Hz, 1H); 2.56 (m, 2H); 2.67 (dt, J=10.5, 2.4 Hz, 2H); 3.15 (d, J=13.5Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.86 (d, J=13.5 Hz, 1H); 5.15(s, 1H); 7.19 (m, 5H); 7.29 (m, 4H); 7.33 (br t, J=7.4 Hz, 2H); 7.46 (d,J=8.1 Hz, 2H).

EXAMPLE 8

[0279]4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-methoxybenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide

[0280] (72.44%). Calc. for C₃₂H₄₁N₃O₂: C, 76.92; H, 8.27; N, 8.41. FoundC, 76.98; H, 8.38; N, 8.42%. ¹H NMR (CDCl₃, 600 MHz); δ 1.07 (d, J=6.2Hz, 3H); 1.11 (d, J=6.1 Hz, 3H, overlapping br m, 3H); 1.23 (br m, 3H);1.91 (br t, J=10.2 Hz, 1H); 1.99 (dd, J=11.0, 8.6 Hz, 1H); 2.52 (br m,2H); 2.64 (dd, J=11.5, 2.6 Hz, 1H); 2.68 (dd, J=11.1, 2.6 Hz, 1H); 3.13(d, J=12.9 Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.79 (s, 3H); 3.85(d, J=13.5 Hz, 1H); 5.17 (s, 1H); 6.82 (d, J=8.5 Hz, 2H); 7.19 (d, J=8.3Hz, 4H); 7.29 (m, 5H); 7.46 (d, J=8.1 Hz, 2H).

EXAMPLE 9

[0281]4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide

[0282] A solution of 3-bromophenol (400 g, 2.31 mol),tert-butylchlorodimethylsilane (391 g, 2.54 mol), and imidazole (346 g,5.08 mol) in 5000 mL of dichloromethane was stirred overnight at roomtemperature. The reaction solution was poured into 2000 mL of water andthe layers were separated. The organic layer was washed with 1N aqueoussodium hydroxide solution (3×1500 mL) and water (2×1500 mL) beforepassing through a pad of silica gel (400 g, silica 60, 230-400 mesh).The silica gel was washed with dichloromethane (2×500 mL), the filtrateswere combined and the solvent removed under reduced pressure to give 669g (98.4%) of 3-(bromophenoxy)-tert-butyldimethylsilane as a clear paleyellow liquid. NMR (300 MHz, CDCl₃): δ 0.2 (s,6H); 1.0 (s,9H); 6.75(m,1H); 7.0 (br s, 1H); 7.1 (m,2H).3-tert-Butyldimethylsilyloxyphenylmagnesium bromide was formed by theslow addition of a mixture 3-bromophenoxy-tert-butyldimethylsilane (27.3g, 92.6 mmol) and dibromoethane (3.45 g, 18.4 mmol) in 100 mL ofinhibitor-free anhydrous tetrahydrofuran to a solution of magnesiumturnings (3.57 g, 147 mmol) in 200 mL of inhibitor-free anhydroustetrahydrofuran at reflux. After stirring for one hour at reflux thelight brown clear mixture was cooled to room temperature.

[0283] 4-Carboxybenzaldehyde (100.3 g, 0.67 mol) was dissolved/suspendedin toluene (1200 mL, dimethylformamide (0.15 mL) added and thesuspension stirred during the dropwise addition of thionyl chloride(53.5 mL, 87.2 g, 0.73 mol). The reaction mixture was heated to refluxunder nitrogen and stirred for 2 h, during which time much, but not allof the aldehydo-acid passed into solution. A further quantity of thionylchloride (20 mL, 32.6 g, 0.27 mol) was added and reflux continuedovernight. The clear reaction mixture was evaporated, and the residuedissolved in anhydrous tetrahydrofuran (1500 mL). The solution wascooled in an ice/water bath and diethylamine (173 mL, 122 g, 1.67 mol(2.5 equivalents)) was added dropwise to the stirred solution. Theice-bath was removed and stirring continued for 2.5 h. The reactionmixture was filtered to remove the white crystalline diethylaminehydrochloride by-product. The crystals were washed with ethyl acetate(2×600 mL), and the washings set aside. The tetrahydrofuran filtrate wasevaporated, and the residue dissolved in the ethyl acetate washings. Thesolution was washed sequentially with 1 M-hydrochloric acid (2×600 mL),water 2×300 mL), dilute sodium carbonate solution (saturated:H₂O, 1:1,2×600 mL), water (2×300 mL) and saturated sodium chloride solution (300mL). The organic layer was separated, dried over anhydrous sodiumsulfate and evaporated to yield 4-formyl-N,N-diethylbenzamide as a palebrown oil which was used without further purification. (Yield 115.7 g,84%)

[0284] In a 1000 mL round bottom flask fitted with a condenser andDean-Stark trap were combined 4-formyl-N,N-diethylbenzamide (9.50 g,46.3 mmol), benzotriazole (5.51 g, 46.3 mmol), and(2R,5S)-1-allyl-2,5-dimethylpiperazine (7.15 g, 46.3 mmol, ChirotechTechnology, Ltd., Cambridge, England) with 400 mL of toluene. Thereaction was heated to reflux under nitrogen until no additional waterwas observed in the trap (ca. 2 hours). The reaction was cooled to roomtemperature and concentrated under vacuum to leave a volume ofapproximately 50 mL. Anhydrous tetrahydrofuran (100 mL) was added to theflask under nitrogen with stirring to dissolve all residue. The solutionof benzotriazole adduct was added to the solution of3-tert-butyldimethylsilyloxyphenylmagnesium bromide (above) at roomtemperature via double-ended needle. After stirring for 2 hours, thereaction was quenched by addition of 20 mL of saturated aqueous ammoniumchloride. Anhydrous magnesium sulfate was added and the reaction wasfiltered. Solvent was removed under vacuum and the residue wasredissolved in 800 mL of ethyl acetate. The ethyl acetate solution waswashed with 4×200 mL of 1 M sodium hydroxide, 200 mL of water, and 200mL of saturated aqueous sodium chloride. The organic layer was driedover anhydrous magnesium sulfate and the solvent was removed to give32.7 g of dark oil. The oil was dissolved in 250 mL of tetrahydrofuranand 250 mL of 3 M hydrochloric acid and stirred for 2 hours at roomtemperature. The reaction solution was extracted with 3×250 mL of 2:1diethyl ether/ethyl acetate. Ethyl acetate (300 mL) was added to theaqueous layer and pH was adjusted to 8 with aqueous sodium hydroxide.Layers were separated and the aqueous portion was extracted with another3×300 mL of ethyl acetate. The combined organic extracts were washedwith saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, and the solvent was removed under vacuum to give 12.4 g ofbrown residue. The residue was purified by chromatography on 300 g ofsilica gel, eluting with a gradient of 1-15% ethanol in dichloromethane,to give 5.54 g of4-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamideas a colorless gum (27% from 4-formyl-N,N-diethylbenzamide).

[0285]4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidehydrochloride (0.97 g, 2.0 mmol) was dissolved in methylene chloride (10mL) under nitrogen and triethylamine (0.919 mL, 0.667 g, 6.6 mmol) wasadded followed by N-phenyl bis(trifluoromethanesulfonimide) (0.785 g,2.2 mmol). The reaction mixture was stirred at room temperatureovernight and evaporated to dryness. The residue was dissolved in ethylacetate (20 mL) and extracted with 5% sodium carbonate solution (2×15mL). The organic layer was separated, dried over anhydrous sodiumsulfate and evaporated to yield a viscous amber oil. The residue wasdissolved in methylene chloride (5 mL), applied to a column of silicagel (4×30 cm), and eluted with ethanol/methylene chloride (2:98 v/v).Pure fractions containing desired product, as evidenced by t.l.c.(silica gel, EM60F₂₅₄, 2% NH₄OH in ethyl acetate, R_(f)=0.78) wereevaporated to dryness to yield4-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide(0.72 g) as a yellow/amber oil. ¹H NMR (CDCl₃, 500 MHz); δ 1.00 (d,J=6.2 Hz, 3H); 1.12 (br m, 3H); 1.21 (d, J=6.1 Hz, 3H); 1.25 (br m, 3H);1.83 (t, J=10.6 Hz, 1H); 2.60 (m, 3H); 2.91 (dd J=11.4, 2.7, 1H); 3.02(m, 1H); 3.18 (br s, 2H); 3.28 (br m, 2H); 3.46 (dd, J=13.7, 5.5 Hz,1H); 3.55 (br m, 2H); 5.25 (m, 2H); 5.31 (s, 1H); 5.88 (m, 1H); 7.02 (d,J=7.7 Hz, 1H); 7.05 (s, 1H); 7.23 (m, 2H); 7.32 (d, J=8.1 Hz, 2H); 7.40(d, J=8.1 Hz, 2H); 7.46 (t, J=7.9 Hz, 1H).

EXAMPLE 10

[0286]4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxybenzyl)-N,N-diethylbenzamide

[0287] The compound of Example 9 was de-allylated by the method of Genet[J. P. Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36,1267-1270 (1995)] as follows. A solution of4-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide(Example 9, 0.72 g, 1.286 mmol) and thiosalicylic acid (234.7 mg, 1.522mmol) in anhydrous tetrahydrofuran (4 mL) was stirred under nitrogen for3 h at room temperature with a catalyst solution prepared by dissolutionof bis(dibenzylidineacetone)palladium (36.46 mg, 0.0634 mmol) and1,4-bis(diphenylphosphino)butane (27.04 mg, 0.0634 mmol) intetrahydrofuran (0.5 mL). The reaction mixture was evaporated todryness, the residue was dissolved in a mixture of ethyl acetate/ether(1:3, 20 mL) and extracted with 5% sodium carbonate solution (2×15 mL).The organic layer was diluted with two volumes of pentane and extractedwith 3M-hydrochloric acid (5×4 mL). The aqueous solution was adjusted topH 9-10 with concentrated ammonia solution and extracted with methylenechloride (3×10 mL). The combined organic extracts were dried overanhydrous sodium sulfate and evaporated to yield4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxybenzyl)-N,N-diethylbenzamide as a brittle pale yellow foam (0.63 g). Theproduct showed a single spot on thin layer chromatography (silica gel,EM60F₂₆₄, 2% NH₄OH in ethyl acetate, R_(f)=0.33). ¹H NMR (CDCl₃, 500MHz); δ 0.95 (d, J=6 Hz, 3H); 1.13 (br m, 3H); 1.20 (d, J=6.1 Hz, 3H);1.26 (br m, 3H); 1.50 (t, J=9.7 Hz, 1H); 2.31 (m, 1H); 2.64 (dd J=11.3,2.5, 1H); 2.71 (m,1H); 2.95 (m, 1H); 3.29 (br m, 2H); 3.56 (br m, 2H);5.43 (s, 1H); 7.04 (m, 1H); 7.21 (d, J=7.7, 1H); 7.24 (dd, J=8.2, 2.2Hz, 1H); 7.34 (d, J=8.2 Hz, 2H); 7.42 (d, J=8.1 Hz, 2H); 7.48 (t, J=8Hz, 1H).

EXAMPLE 11

[0288]4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

[0289]4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxy-benzyl)-N,N-diethylbenzamide(Example 10, 527.6 mg, 1.0 mmol) was dissolved in acetonitrile (4.0 mL)with sodium iodide (30 mg, 0.2 mmol). The suspension was stirred duringthe addition of triethylamine (800 μL, 580.8 mg, 5.74 mmol), followed by4-fluorobenzyl bromide (249 μL, 378 mg, 2.0 mmol). The reaction mixturewas sealed under nitrogen and stirred overnight at room temperature. Thereaction mixture was evaporated to dryness and and the residue dissolvedin ethyl acetate (10 mL). The organic solution was washed with saturatedaqueous sodium bicarbonate solution (2×5 mL) and saturated sodiumchloride solution (5 mL), dried over anhydrous sodium sulfate andevaporated to a golden oil (a single spot on silica gel, EM60F₂₆₄, 2%NH₄OH in ethyl acetate, R_(f)=0.86). This intermediate4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide(608.9 mg) was used without further purification. The oil was dissolvedin ethanol (8 mL) and aqueous 2.5 M (10%) sodium hydroxide solution (5mL, 12.5 mmol) was added. The reaction mixture was stirred at roomtemperature for 3.5 h and the ethanol was removed by evaporation. Theoily suspension of the sodium salt was clarified by the addition ofwater (7.5 mL), and the pH of the solution was adjusted to 8.5-9 by thepassage of gaseous carbon dioxide (from dry ice). The copious whiteprecipitate was collected by filtration, washed well with water, anddried under vacuum (2 mm Hg) at room temperature overnight to yield4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamideas a white solid (423.6 mg, 84%). Calc. for C₃₁H₃₈FN₃O₂ C, 73.93; H,7.61; N, 8.34. Found C, 73.91; H, 7.65; N, 8.21% ¹H NMR (CDCl₃, 600MHz); δ 1.05 (d, J=6.3 Hz, 3H); 1.07 (d, J=6.3 Hz, 3H); 1.11 (br m, 3H);1.25 (br m, 3H); 1.97 (m, 2H); 2.53 (br m, 1H); 2.57 (br m, 1H); 2.61(dd, J=9, 2.6 Hz, 1H); 2.65 (dd, J=9, 2.4 Hz, 1H); 3.14 (d, J=13 Hz,1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.87 (d, J=13 Hz, 1H); 5.13 (s,1H); 6.62 (s, 1H); 6.70 (m, 2H); 6.96 (t, J=8.5 Hz, 2H); 7.13 (t, J=7.8Hz, 1H); 7.24 (m, 2H); 7.28 (d, J=8.2 Hz, 2H); 7.43 (d, J=8.1 Hz, 2H).

EXAMPLE 12

[0290]4-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

[0291] This compound was prepared from4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide(Example 10) by a procedure similar to that of Example 11(88.5%). Calc.for C₃₁H₃₉N₃O₂ 0.9H₂O: C,74.19; H, 8.19; N, 8.37. Found C, 74.20; H,7.88; N, 8.25%. ¹H NMR (CDCl₃, 300 MHz); δ 1.03 (d, J=6.1 Hz, 3H); 1.09(d, J=6.1 Hz, 3H); 1.12 (br m, 3H); 1.24 (br m, 3H); 1.99 (m, 2H); 2.53(br m, 2H); 2.60 (dd, J=9, 2 Hz, 1H); 2.65 (dd, J=9, 2 Hz, 1H); 3.17 (d,J=13 Hz, 1H); 3.29 (br m, 2H); 3.55 (br m, 2H); 3.95 (d, J=13 Hz, 1H);5.13 (s, 1H); 6.55 (s, 1H); 6.64 (m, 2H); 7.10 (t, J=7.7 Hz, 2H); 7.13(m, 1H); 7.24 (m, 5H); 7.45 (d, J=8.1 Hz, 2H).

EXAMPLE 13

[0292]4-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl)benzoicacid

[0293]4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxy-benzyl)-N,N-diethylbenzamide(Example 10, 844 mg, 1.6 mmol) in acetonitrile (8 mL) was added tosodium iodide (45 mg, 0.3 mmol) and stirred during the addition oftriethylamine (1.0 mL, 726 mg, 7.17 mol), followed by methyl4-(bromomethyl benzoate (916.3 mg, 4.0 mmol). The reaction mixture wassealed under nitrogen and stirred at ambient temperature for 5 days. Thesolvent was removed by evaporation and the residue was partitionedbetween ethyl acetate (10 mL) and saturated aqueous sodium bicarbonatesolution (3 mL). The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (3×10 mL). The combined organicextracts were dried over anhydrous sodium sulfate and evaporated todryness. The residue was dissolved in ethyl acetate (5 mL) and appliedto an intermediate (4×15 cm) Biotage silica column and eluted with ethylacetate. Fractions containing the product, as evidenced by t.l.c.(silica, EM60F₂₅₄, 100% EtOAc, Rf=0.74) were evaporated to dryness anddried at room temperature and 2 mm Hg to yield methyl4-{(2R,5S)-4-[(R)-(4-diethylcarbamoylphenyl)(3-(trifluoromethylsulfonyloxy)phenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoate as a rigidwhite foam. The solid (1.09 g, 1.615 mmol) was dissolved in ethanol (10mL) and sodium hydroxide solution (2.5 M, 6.46 mL, 16.16 mmol) was addedin approximately 1 mL aliquots. The slightly turbid reaction mixtureclarified about 5 min after the last addition to yield a yellow solutionwhich was stirred for 16 h at ambient temperature. The solution wasdiluted with an equal volume of water and the ethanol was removed byevaporation along with an estimated 50% of the aqueous volume. The pH ofthe solution was adjusted to 4 with 3 M hydrochloric acid, to yield aflocculent white solid, which was collected by filtration and washedsparingly with cold water. After removal of granular solid from thefilter, the remaining small amount of gummy material was removed fromthe filter, sonicated with water (˜1 mL) to yield a fine solid that wascollected by filtration. After drying at room temperature and 5 mm Hg,both samples were shown to be identical by HPLC (Zorbax C-8, isocratic40% 0.01 M NH₄OAc in MeOH, 3 min: gradient to 100% MeOH, 45 min:isocratic MeOH 5 min. 1.0 mL/min: λ^(obs)=210 nm, Rt=10.58 min) andcombined to yield the title compound (888 mg, 85.9% from4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide). Calc. for C₃₂H₃₉N₃O₄ 1.5 NaCl 1.6H₂O:C, 59.48; H, 6.58; N, 6.50. Found C, 59.50; H, 6.45; N, 6.32% ¹H NMR((CD₃)₂SO+20% v/v 1-M NaOD in D₂O, 300 MHz); δ 0.93 (d, J=6.0 Hz, 3H);0.98 (d, J=5.9 Hz, 3H; both doublets overlapping br m, 6H); 1.9 (m, 2H);2.54 (m, 2H, partially obscured by DMSO); 3.13 (br m, 2H); 3.22 (d,J=14.2 Hz, 1H); 3.34 (br m, 2H); 3.71 (d, J=14.0 Hz, 1H); 4.66 (s, 1H);5.97 (d, J=6.9 Hz, 1H); 6.16 (d, J=7.9, 1H); 6.23 (s, 1H); 6.72 (t,J=7.7 Hz, 1H); 7.16 (d, J=7.8 Hz, 4H); 7.38 (d, J=8.1 Hz, 2H); 7.72 (d,J=8.1 Hz, 2H). Mass spectrum: (ESI−, DP-120V, MeOH); m/z: 529.0, (M+,100%); 528, ((M−1)+, 57%); 512.6, ((M−17)+, 95%).

EXAMPLE 14

[0294]3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylamino-carbonyl)benzyl)phenoxyaceticacid

[0295] Sodium hydride (60% dispersion in oil, 250 mg (150 mg NaH, 6.25mmol)) was washed with anhydrous tetrahydrofuran (2×5 mL) and anhydroustetrahydrofuran (10 mL) was added as supernatant.4-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidehydrochloride (435 mg, 1.0 mmol, prepared in Example 9) was dissolved inthe stirred suspension, and when effervescence had subsided, sodiumiodide (15 mg, 0.1 mmol) was added. Methyl chloroacetate (350 μL, 434mg, 4 mmol) was added to the stirred suspension under nitrogen and thereaction was stirred overnight at ambient temperature. The reactionmixture was partially neutralized by the passage of carbon dioxide gas(from dry ice), then glacial acetic acid added until the suspensionshowed a pH of 5 as measured by moistened indicator strips. The reactionmixture was evaporated to dryness, and the residue partitioned betweenethyl acetate (10 mL) and 1 M HCl (5 mL). The organic layer wasextracted with 1 M HCl (2×3 mL) and the pH of the combined acidicextracts was adjusted to 8 with saturated sodium carbonate solution. Theoily aqueous suspension was extracted with ethyl acetate (3×10 mL) andthe combined organic extracts were dried over anhydrous sodium sulfate.The solution was evaporated to a yellow gum. The residue was dissolvedin ethyl acetate and applied to an intermediate (4×15 cm) silica gelBiotage column and eluted with 10% ethanol in ethyl acetate. Fractionscontaining the product, as evidenced by t.l.c. (silica, EM60F₂₅₄, 10%EtOH in EtOAc, Rf=0.52) were evaporated to dryness and dried at roomtemperature and 2 mm Hg to yield methyl 3-((alpha-R)-alpha-((2S,SR)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylaminocarbonyl)benzyl)phenoxyacetateas a clear pale yellow gum. The residue was dissolved in ethanol (4 mL)and aqueous sodium hydroxide solution (2.5-M, 1.0 mL, 2.5 mmol) andstirred at room temperature for 6 h. The solution was evaporated toremove the bulk of the ethanol, and water (5 mL) added. Evaporation wascontinued until approximately 4 mL of solution remained, a further 8 mLof water added, and the solution was evaporated to approximately halfits volume to ensure complete removal of ethanol. A small amount ofsuspended solid was removed by filtration, and the pH of the solutionwas adjusted to 6 with 3 M HCl. The solution was evaporated to drynessand the residue evaporated several times with absolute ethanol to ensureremoval of water. The residue was extracted with ethanol (3×20 mL) andthe combined ethanol extracts were filtered and evaporated to dryness.The gummy residue was triturated with ethyl acetate (5 mL), filtered,evaporated, and dried under high vacuum to yield3-((alpha-R)-alpha-((2S,SR)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylaminocarbonyl)benzyl)phenoxyaceticacid as a brittle white foam (52 mg, 9.5%). Calc. for C₂₉H₃₉N₃O₄ 0.9NaCl 0.5H₂O: C, 63.45; H, 7.20; N, 7.65. Found C, 63.83; H, 7.19; N,7.25% ¹H NMR (0.1-M NaOD in D₂O, 300 MHz); δ 0.86 (d, J=6.3 Hz, 3H);0.94 (t, J=7.1 Hz, 3H); 1.01 (d, J=6.1 Hz, 3H); 1.09 (t, J=7.2 Hz, 3H);1.81 (t, J=11.3 Hz, 1H); 2.09 (t, J=11.2 Hz, 1H); 2.43 (m, 2H); 2.73 (m,3H); 3.13 (q, J=7.1 Hz, 2H); 3.25 (dd, J=13.5, 5.8 Hz, 1H); 3.38 (q,J=7.2 Hz, 2H); 4.32 (s, 2H); 5.09 (s, 1H): 5.14 (d, J=7.8 Hz, 1H); 5.24(s, 1H); 5.74 (m, 1H); 6.73 (s, 1H); 6.80 (s, 2H); 7.21 (m, 3H); 7.32(d, J=8.2 Hz, 2H). Mass spectrum: (ESI−, −5 KV, MeOH); m/z: 493, (M+,25%); 492.5, ((M−1)+, 100%).

EXAMPLE 15

[0296]3-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-4-(diethylaminocarbonyl)benzyl)phenoxyacetic acid

[0297] Alkylation of4-((alpha-R)-alpha-((2S,5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(Example 12) with ethyl iodoacetate, and subsequent hydrolysis of theester as in Example 14 gave the title compound (84.6%) ¹H NMR (0.1-MNaOD in CD₃OD, 300 MHz); δ 1.10 (d, J=5.0 Hz, 3H); 1.11 (d, J=5.8 Hz,3H; both doublets superimposed on m, 3H); 1.23 (m, 3H); 2.03 (m, 2H);2.57 (m, 2H); 2.69 (m, 2H); 3.30 (m, 3H, superimposed on br m, 2H); 3.88(d, J=13.1 Hz, 1H); 4.35 (s, 2H); 5.16 (s, 1H): 6.83 (m, 2H); 6.88 (s,1H); 7.25 (m, 8H); 7.52 (d, J=8.1 Hz, 2H). Mass spectrum: (PFAB,glycerol matrix subtracted): m/z: 544.8, ((M+1)⁺, 82%).

EXAMPLE 16

[0298] 3-((alpha-R)-4-(Diethylaminocarbonyl)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)benzyl)phenoxyaceticacid By an essentially similar procedure to that of Example 15,3-((alpha-R)-4-(diethylaminocarbonyl)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-benzyl)phenoxyaceticacid was made from4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(product from Example 11). Calc. for C₃₃H₄₀FN₃O₄ 0.6 NaCl 1.2H₂O: C,64.10; H, 6.91; N, 6.80; F, 3.07. Found C, 64.19; H, 6.91; N, 6.49; F,3.06%. ¹H NMR (D₂O, 300 MHz); δ 0.95 (t, J=6.6 Hz, 3H); 1.04 (d, J=6.1Hz, 3H); 1.09 (d, J=6.3 Hz, 3H superimposed on 1.102 (t, J=7.2 Hz, 3H));2.10 (br m, 1H); 2.58 (br m, 1H); 2.79 (br t, J=10.8 Hz, 1H); 2.93 (brd, J=12.5 Hz, 1H); 3.14 (d, J=6.5 Hz, 1H, superimposed on m, 2H); 3.39(d, J=7.3 Hz, 1H, superimposed on m, 3H); 4.00 (m, 1H); 4.40 (s, 2H);5.33 (br s, 1H): 6.76 (br m, 1H) overlapping 6.83 (m, 2H); 7.10 (m, 2H);7.22 (m, 3H); 7.37 (m, 4H). Mass spectrum (PFAB, glycerol matrixsubtracted); m/z: 562.1, (M+, 82%); 340.2 ((M−222)+, 40%); 109.0(C₇H₆F+, 100%).

EXAMPLE 17

[0299]N,N-Diethyl-3-((R)-((2S,5R)-2,5-dimethyl-4-(3-hydroxybenzyl)piperazin-1-yl)(3-hydroxyphenyl)methyl)benzamide

[0300] 3-Carboxybenzaldehyde (15.01 g, 100 mmol) was added to a 250 mL,3-necked round bottom flask and stirred under nitrogen in 110 mL oftoluene. Thionyl chloride (8.75 mL, 120 mmol) was added to the mixture,followed by the addition of 6 drops of DMF. A reflux condenser fittedwith a calcium chloride drying tube was placed on the flask. Thereaction was placed in an oil bath and heated at a bath temperaturemaintained below 120° C. The mixture was allowed to reflux for 1 hourafter a clear solution was obtained and then cooled to room temperature.The solution was diluted with anhydrous toluene, and all volatiles wereremoved under vacuum.

[0301] The crude acid chloride was dissolved in 200 mL of drytetrahydrofuran and cooled in an ice/water bath. Triethylamine (27.88mL, 200 mmol) in 70 mL of dry tetrahydrofuran was added dropwise via anaddition funnel, followed by diethylamine (10.45 mL, 100 mmol). Thecloudy solution was allowed to warm to room temperature over 1 hour andstirred overnight. Water was added and the product was extracted withdichloromethane. The organic layer was washed with water and saturatedsodium chloride solution and dried over sodium sulfate, and the solventwas removed under vacuum. 3-Formyl-N,N-diethylbenzamide (17.72 g) wasobtained as a light golden oil (86% unchromatographed yield). ¹H NMR(300 MHz, DMSO-d₆): δ 1.04-1.18 (m, 6H); 3.17-3.45 (m, 4H); 7.65-7.66(m, 2H); 7.85 (s, 1H); 7.93-7.94 (m, 1H); 10.03 (s, 1H).

[0302] A 12 L, 3-necked round bottom flask was charged withtrans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had beenrecrystallized from toluene to mp=115-119° C., and 600 mL of water. Theflask was cooled in an ice bath and a solution of methanesulfonic acid(1290 g, 13.4 mol) in 600 mL of water was added slowly with stirring andcooling to maintain the temperature below 40° C. The solution was cooledto 20° C. and 800 mL of ethanol was added. A 500 mL addition funnel wasfilled with 60% aqueous potassium acetate from a 2 L reservoir of thesolution, and potassium acetate was added to the reaction flask toadjust the pH to 4.0. A second addition funnel was charged with asolution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL oftetrahydrofuran. The ethyl chloroformate and potassium acetate solutionswere simultaneously added dropwise with adjustment of rate to maintainthe reaction solution at pH 4.0±0.1, with cooling as necessary tomaintain temperature at 25° C. After addition of the ethyl chloroformatewas complete, the reaction was stirred for 1 hour with continuedaddition of potassium acetate solution to maintain a pH of 4.0. Theorganic solvents were removed by distillation under vacuum. Theremaining aqueous solution was washed with 1500 mL of ethyl acetate toremove any bis-carbamate impurity. The ethyl acetate wash was extractedwith two 500 mL portions of 1 M hydrochloric acid to recover desiredproduct. The acid extracts were combined with the original aqueoussolution and the pH was adjusted to 11 by addition of 10 M sodiumhydroxide, with cooling to maintain temperature below 40° C. The aqueoussolution was extracted with two 1500 mL portions of ethyl acetate, thecombined extracts were dried over magnesium sulfate, and the solvent wasremoved to give 927 g (74%) ethyltrans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.

[0303] A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate(643 g, 3.45 mol), allyl bromide (328 mL, 3.80 mol), and sodiumcarbonate (440 g, 4.15 mol) in 2500 mL of acetonitrile was heated atreflux for 1.5 hours. The reaction was cooled to room temperature,filtered, and the solvent removed under vacuum. The residue wasdissolved in 4000 mL of dichloromethane and washed with two 500 mLportions of 1 M sodium hydroxide. The dichloromethane solution was driedover magnesium sulfate and the solvent was removed to give 630 g (81%)of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.

[0304] Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g,2.78 mol) was added to a solution of 87% potassium hydroxide pellets(2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5hours. Carbon dioxide evolution was observed for the first 0.5-1 hour ofheating. The reaction was cooled below reflux temperature and 2000 mL oftoluene was carefully added. Ethanol was removed by azeotropicdistillation at 105 C, while adding an additional 4000 mL of toluene tothe reaction flask during the course of the distillation. Aftercollection of 9000 mL of distillate, the reaction was cooled to 100 Cand 1000 mL of toluene was carefully added. The solution was slowlycooled to 5 C and maintained at 5° C. for 30 minutes. The solution wasfiltered, and the filter cake was washed with an additional 1500 mL oftoluene. The filtrate was washed with 1000 mL of water, dried overmagnesium sulfate, and the solvent was removed to give 296 g (69%) oftrans-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz,DMSO-d₆): δ 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t, J=1Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=1 Hz, 1H); 2.6-2.8 (m, 4H); 3.33 (dd,J=5 Hz, J₂=14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz, 1H) 5.8(m, 1H).

[0305] Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., SouthPlainfield, N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot (˜60 C) 95%ethanol (16 L) and racemic trans-1-allyl-2,5-dimethylpiperazine (500 g,3.2 mol) was added in several portions (caution: exothermic). The hotsolution was seeded with crystals of the diastereoisomerically pure salt(obtained from a previous small-scale resolution) and cooled to roomtemperature over 2-3 hours. The solution was slowly stirred for 2 daysat room temperature. The resulting salt was collected by filtration,washed twice with 95% ethanol, and dried under vacuum to give 826.5 g ofa white solid (47%). The process was repeated with a second batch of thedi-p-toluoyl-D-tartaric acid and racemictrans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).

[0306] The total of 1695 g of salt was divided into three batches andeach batch was recrystallized twice in the following fashion. The saltwas dissolved in refluxing 95% ethanol (˜2.7 L/100 g of salt), andapproximately half of the ethanol was removed by distillation. (Note:vigorous stirring was necessary during distillation to preventcrystallization on the vessel wall.) The hot solution was seeded withcrystals of the pure diastereomeric salt, cooled to room temperature,and stirred slowly for 2 days before collecting the salt by filtration.(Note: a subsequent experiment suggested that crystallization time canbe reduced from 2 days to 8 hours.) The total amount recovered was 1151g. The salt was dissolved in 3 L of 2 M aqueous sodium hydroxide, andthe aqueous solution was extracted with four 1 L portions ofdichloromethane. The organic extracts were combined, dried over sodiumsulfate, and solvent removed by rotary evaporation (temperature <20° C.)to give 293 g (29% based on racemic weight) of(2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil. [α]_(D) ²⁰=−55.1(abs. ethanol, c=1.2). The trifluoroacetamide of the product wasprepared with trifluoroacetic anhydride and analyzed by chiral capillarygas chromatography (Chiraldex B-PH column, 20 m×0.32 mm, AdvancedSeparation Technologies Inc., Whippany, N.J., 120° C.) indicating anenantiopurity of >99% ee (retention time of desired enantiomer, 11.7min; other enantiomer, 10.7 min).

[0307] A solution of 3-bromophenol (500 g, 2.89 mol),tert.-butylchlorodimethylsilane (436 g, 2.89 mol), and imidazole (500 g,7.22 mol) in 500 mL of dimethylformamide was stirred overnight at roomtemperature. The reaction solution was poured into 3000 mL of water andextracted with two 2000 mL portions of diethyl ether. The combinedeither extracts were dried over sodium sulfate and the solvent removedto give 846 g of 3-(bromophenoxy)-tert.-butyldimethylsilane as a paleyellow liquid. NMR (300 MHz, CDCl₃): δ 0.2 (s,6H); 1.0 (s,9H); 6.75(m,1H); 7.0 (br s, 1H); 7.1 (m,2H). 3-(tert-butyldimethylsilyloxy)phenylmagnesium bromide was formed by the slow addition of 2.7 Mn-butyllithium in heptane (150 mL, 405 mmol) to a solution of3-bromophenoxy-tert-butyldimethylsilane (123.44 g, 429 mmol) in 500 mLanhydrous tetrahydrofuran at −70° C. After stirring 45 min. this coldsolution was siphoned under nitrogen into a slurry of magnesium bromideetherate (110.62 g, 428 mmol) in 650 mL anhydrous tetrahydrofuran atroom temperature, and stirred for 45 min.

[0308] 2R,5s-1-allyl-2,5-dimethylpiperazine (2.31 g, 15 mmol),benzotriazole (1.80 g, 15.15 mmol, 1.01 eq., Aldrich), and3-formyl-N,N-diethylbenzamide (3.08 g, 15 mmol) were mixed in 150 mL ofdry toluene with two drops of triethylamine. The mixture was placed inan oil bath maintained below 140° C. (bath temperature). The flask wasattached to a Dean-Stark trap and reflux condenser to allow theazeotropic removal of water. The mixture was refluxed for 2-3 hours,under a nitrogen atmosphere, then the majority of the toluene wasremoved under reduced pressure. The crude adduct was used in thefollowing procedure without isolation.

[0309] The crude benzotriazole adduct was dissolved in ˜20 mL ofanhydrous tetrahydrofuran under nitrogen and added to a solution of3-(tert-butyldimethylsilyloxy)phenyl magnesium bromide (1.75 equiv.) viaa double-ended needle. After stirring under nitrogen at room temperaturefor 2 hours, the reaction was quenched with 6-8 mL of saturated ammoniumchloride solution. Having stirred this for about half an hour, agenerous amount of anhydrous magnesium sulfate was added. Filtering andconcentrating the solution under reduced pressure gave the crude productcontaminated with benzotriazole. This residue was dissolved in ethylacetate and extracted with 10% aqueous NaOH solution three times toremove most of the benzotriazole. The organic layer was washed withsaturated sodium chloride solution, dried over sodium sulfate/magnesiumsulfate, and the ethyl acetate was removed under reduced pressure.

[0310] The t-butyldimethylsilyl protecting group was removed bydissolving the residue in 80 mL of tetrahydrofuran and adding 80 mL of3N aqueous HCl at room temperature. The solution warmed upon acidaddition. The mixture was stirred for 90 minutes at room temperature.The reaction was concentrated under reduced pressure to remove most ofthe organic solvent. The residue was partitioned between water and asolution of diethyl ether: ethyl acetate/3:2. The acidic aqueous layerwas extracted twice with a solution of diethyl ether: ethyl acetate/3:2.The aqueous layer was adjusted to pH=2 using aqueous NaOH solution, atwhich point cloudiness persisted and a dark oil began to precipitate.Methylene chloride (˜100 mL) was added and stirred briskly. This wasseparated and the aqueous layer was again extracted with 100 mLmethylene chloride. Water (100 mL) was added to the combined organicextracts, and while stirring vigorously, was adjusted to pH=9 usingaqueous NaOH solution. The organic layer was separated and the aqueouslayer was again extracted with 100 mL methylene chloride. The combinedmethylene chloride extract was dried over sodium sulfate/magnesiumsulfate, and the solvent was evaporated under reduced pressure. Thecrude material was chromatographed on a silica gel column (20-25 g ofsilica gel per gram of crude material) eluting first with methylenechloride, then with 20% ethyl acetate in methylene chloride to removethe less polar contaminant. Then, the column was eluted with a solutionof ethyl acetate containing 2% ammonium hydroxide (solution A) in agradient with methylene chloride (solution B), quickly increasing inpolarity from 25% to 100% (solution A in B). The desired fractions werecombined and the solvent was removed under reduced pressure. A 10:1mixture of diastereomers (approx. 2.01 g) was obtained. Pure product wasobtained by crystallization from a hot solution of ethyl acetate (5-10mL) followed by slow addition of heptane (10-20 mL) and gradual coolingto give 1.35 g of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamideas an off-white crystalline solid with >98% isomeric purity (asdetermined by NMR). NMR (400 MHz, DMSO-d₆): δ 0.91 (d, J=6.2 Hz, 3H);0.99 (br s, 3H); 1.05 (d, J=6.2 Hz, 3H); 1.09 (br s, 3H); 1.84 (dd,J₁=7.3 Hz, J₂=1 0.9 Hz, 1H); 2.06 (dd, J₁=7.3 Hz, J₂=10.9 Hz, 1H); 2.48(m, 1H); 2.51 (dd, J₁=2.7 Hz, J₂=10.9 Hz, 1H); 2.58 (br s, 1H); 2.70(dd, J₁=2.7 Hz, J₂=10.9 Hz, 1H); 2.81 (dd, J₁=17.0 Hz, J₂=13.9 Hz, 1H);3.12 (br s, 2H); 3.15 (dd, J₁=5.1 Hz, J₂=13.9 Hz, 1H); 3.38 (br s, 2H);4.97 (br s, 1H); 5.07 (d, J=10.2 Hz, 1H), 5.14 (d,J=16.9 Hz, 1H);5.70-5.82 (m, 1H); 6.64 (dd, J₁=2.1 Hz, J₂=8.0 Hz, 1H); 6.65 (s, 1H);6.68 (d, J=7.7 Hz, 1H); 7.11 (t, J=8.0 Hz, 1H); 7.14 (d, J=7.6 Hz, 1H);7.30 (s, 1H); 7.33 (t, J=7.6 Hz, 1H); 7.39 (d, J=8.0 Hz, 1H); 9.31 (s,1H).

[0311]3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (4.35 g, 10 mmol), N-phenylbis(trifluoromethanesulfonimide)(3.82 g, 10.7 mmol), and triethylamine (3.1 mL, 22 mmol) were dissolvedin 75 mL dichloromethane and stirred overnight at room temperature undernitrogen. After concentrating under reduced pressure, the residue wasdissolved in 100 mL ethyl acetate and washed with Na₂CO₃ solution (3×100mL), water (1×100 mL), and brine (1×100 mL). The solution was dried(Na₂SO₄/MgSO₄) and concentrated under reduced pressure. The residual oilwas purified by chromatography on silica gel (2% NH₄OH in EtOAc/CH₂Cl₂)to give 6.01 g (10.59 mmol) of3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxybenzyl)-N,N-diethylbenzamideas a viscous, golden yellow oil.

[0312] The allyl group was removed using Pd(dba)₂/DPPB in the presenceof thiosalicylic acid by the method of Genet [J. P. Genet, S.Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270(1995)]. The reaction was concentrated and the residue was dissolved in50 mL ethyl acetate and 100 mL diethyl ether. After washing this withNa₂CO₃ solution (3×100 mL) and water (1×100 mL), the organic solutionwas extracted with 3 N HCl (3×20 mL) and 1 N HCl (1×20 mL). The acidicextract was adjusted to pH 8.5 using NaOH solution and extracted withdichloromethane (3×25 mL). The solution was dried (Na₂SO₄/MgSO₄) andconcentrated under reduced pressure. The residual oil was purified bychromatography on silica gel (2% NH₄OH in EtOAc/CH₂Cl₂) to give 4.39 g(8.32 mmol) of3-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxybenzyl)-N,N-diethylbenzamideas a viscous, deep amber-orange colored oil.

[0313] The above free amine (0.70 g, 1.33 mmol) and3-hydroxybenzaldehyde (0.32 g, 2.66 mmol) were placed in a 50 mL flaskand sealed under nitrogen with 15 mL of tetrahydrofuran and 83.75 μl ofacetic acid (1.46 mmol, 1.10 equiv.). The solution was stirred at roomtemperature for 20 minutes, and then sodium triacetoxyborohydride (0.56g, 2.66 mmol) was added and stirred for 4 hours. The reaction solutionwas concentrated under reduced pressure. Ethanol (15 mL) and 10 mL of10% NaOH solution was added to the residue and the reaction was stirredfor 30 minutes. The ethanol was removed under vacuum. Water (25 mL) andethyl acetate (25 mL) were added to the residue, and the pH was adjustedto 8.5 using 6 N HCl. The ethyl acetate layer was separated and theaqueous layer was extracted again with ethyl acetate (2×25 mL). Thecombined ethyl acetate extract was dried (Na₂SO₄/MgSO₄) and concentratedunder reduced pressure. The residual oil was purified by chromatographyon silica gel (EtOAc/CH₂Cl₂) to give 0.52 g (1.04 mmol) of the desiredproduct as a white amorphous solid. The white powdery solid wasprecipitated from ethyl acetate/hexanes. ¹H NMR (DMSO-d₆, 300 MHz); δ0.99 (d, J=6.3 Hz, 3H); 1.02 (d, J=6.3 Hz, 3H, both doublets partiallyoverlapped by br m, 3H); 1.08 (br m, 3H); 1.92 (m, 1H); 1.98 (m, 1H);2.51 (m, 2H); 2.60 (m, 2H); 3.11 (d, J=13.8 Hz, 1H, overlapping br m,2H); 3.30 (br m, 2H, partially obscured by H₂O); 3.67 (d, J=13.5 Hz,1H); 4.97 (s, 1H); 6.56 (d, J=7.8 Hz, 1H); 6.67 (m, 4H); 7.03 (t, J=7.8Hz, 1H); 7.13 (m, 2H); 7.36 (m, 4H); 9.18 (s, 1H); 9.32 (s, 1H). MS:502.1 (M+1, 100%). Calculated for C₃₁H₃₉N₃O₃.0.20 C₄H₈O₂. 0.40 C₆H₁₄: C,74.18; H, 8.41; N, 7.59. Found: C, 74.25; H, 8.36; N, 7.61.

EXAMPLE 18

[0314](−)-4-(αR)-α-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide

[0315] A mixture of 4-carboxybenzaldehyde (100 g, 0.66 mol), 1L ofdimethylformamide and 2L of dichloromethane was cooled in an ice bath.Thionyl chloride (53 mL, 0.73 mol) was added dropwise while stirring.After 18 hours at room temperature, the mixture was cooled again anddiethylamine (275 mL, 2.6 mol) was added dropwise. After stirring atroom temperature for one hour the solvent was evaporated, and theresidue was dissolved in aqueous 0.1 M sodium hydroxide and extractedwith ethyl acetate. The organic layers were washed with water and brine,dried over sodium sulfate and evaporated to give a yellow oil.Chromatography on silica gel with ethanol (0-2%) in dichloromethane gave44.2 g (32%) of 4-formyl-N,N-diethylbenzamide as a yellow oil.

[0316] A solution of 3-bromophenol (500 g, 2.89 mol),tert-butylchlorodimethylsilane (436 g, 2.89 mol), and imidazole (500 g,7.22 mol) in 500 mL of dimethylformamide was stirred overnight at roomtemperature. The reaction solution was poured into 3000 mL of water andextracted with two 2000 mL portions of diethyl ether. The combined etherextracts were dried over sodium sulfate and the solvent removed to give846 g of 3-(bromophenoxy)-tert-butyldimethylsilane as a pale yellowliquid. NMR (300 MHz, CDCl₃): δ 0.2 (s,6H); 1.0 (s,9H); 6.75 (m,1H); 7.0(br s, 1H); 7.1 (m,2H).

[0317] 3-(Bromophenoxy)-tert-butyldimethylsilane (61.7 g, 0.21 mol) wasdissolved in 500 mL of dry tetrahydrofuran under nitrogen and cooled to−78° C. A solution of 1.6 M n-butyllithium in hexane (132 mL, 0.21 mol)was added dropwise at a rate to maintain the temperature below −70° C.The reaction was stirred for thirty minutes after the addition wascomplete and the cold solution was transferred via cannula to anothervessel containing a cold (−78° C.) solution of4-formyl-N,N-diethylbenzamide (44.1 g, 0.21 mol), from above, in 500 mLof dry tetrahydrofuran under nitrogen. The transfer rate was monitoredto maintain the temperature below −70° C. After stirring for one hour at−78° C., the reaction was quenched with saturated aqueous ammoniumchloride, warmed to room temperature and diluted with diethyl ether. Theether layer was washed with water and brine, dried over sodium sulfateand evaporated to give a yellow oil. Chromatography on silica gel withethanol (0-1%) in dichloromethane gave 45.4 g (52%) of4-(3-(tert-butyldimethylsilyloxy)-α-hydroxybenzyl)-N,N-diethylbenzamideas a white solid.

[0318] NMR (200 MHz, CDCl₃) δ: 0.15 (s, 6H); 1.0 (s, 9H); 1.2 (br m,6H); 2.8 (br s, 1H); 3.25 (br m, 2H); 3.5 (br m, 2H); 5.75 (s, 1H); 6.75(d, J=8 Hz, 1H); 6.85 (s, 1H); 7.95 (d, J=8 Hz, 1H); 7.2 (t, J=8 Hz,1H); 7.35 (AB q, J=8 Hz, 4H).

[0319] Thionyl chloride (5.3 mL, 0.075 mol) was added to a solution ofthe benzhydryl alcohol from above (19.75 g, 0.048 mol) in 350 mL ofdichloromethane. After stirring at room temperature overnight thesolvent was evaporated, the residue was redissolved in toluene and againevaporated to drive off excess thionyl chloride and afford crude4-(3-(tert-butyldimethylsilyloxy)-α-chlorobenzyl)-N,N-diethylbenzamide.

[0320] The crude benzhydryl chloride (approximately 0.047 mol),(2R,5R)-2,5-dimethylpiperazine (6.0 g, 0.53 mol), prepared fromL-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) asdescribed in J. Org. Chem. 50: 4909-13 (1985), sodium iodide (9.0 g,0.06 mol), and diisopropylethylamine (14.19 g, 0.11 mol) were heated toreflux in acetonitrile (300 mL) under nitrogen for four hours. Theacetonitrile was evaporated. The residue was dissolved in ethyl acetate(0.5 L) and washed with water. The organic phase was dried over sodiumsulfate and concentrated in vacuo. The residue was dissolved indichloromethane and purified on a short column of silica gel withethanol (5%) in dichloromethane to provide a 1:1 mixture of twobenzhydrylpiperazine diastereomers.

[0321] The mixture of benzhydrylpiperazine epimers (7.6 g, 14.9 mmol)was dissolved in 50 mL of dry tetrahydrofuran with 1.6 mL (18.6 mmol) ofallyl bromide and 5.1 g (36.9 mmol) of sodium carbonate and stirred atroom temperature under nitrogen for 2 days. The reaction solution waspoured into ice water/ethyl acetate and separated. The organic layer wasdried over sodium sulfate, and concentrated in vacuo. The residue wasdissolved in a small amount of dichloromethane and placed on a column ofsilica gel. The diastereomers were separated by elution with a stepwisegradient of ethanol in dichloromethane. The first isomer was eluted with1.3% ethanol in dichloromethane, and the second isomer was obtained with1.6% ethanol in dichloromethane. Fractions containing the second isomerwere combined and the solvent removed in vacuo to give 1.44 g of4-((αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamideas a brown oil.

[0322] NMR (300 MHz, DMSO-d₆): δ 0.12 (s, 6H); 0.89 (m, 12H); 0.93 (d,J=6.5 Hz, 3H); 1.05 (br s, 6H); 2.13 (app t, J=10.4 Hz, 1H); 2.25-2.37(m, 3H); 2.55 (dd, partially obscured by DMSO, 1H); 2.71 (dd, J₁=8.2 Hz,J₂=14.2 Hz, 1H); 2.82 (br d, J=6.2 Hz, 1H); 3.12 (br s, 2H); 3.19 (m,obscured by water, 1H); 3.36 (br s, 2H); 4.55 (s, 1H); 5.08 (d, J=10.8Hz, 1H), 5.14 (d, J=21.5 Hz, 1H); 5.72-5.83 (m, 1H); 6.62 (d, J=8.7 Hz,1H); 6.99 (s, 1H); 7.00 (d, J=8.1 Hz, 1H); 7.12 (t, J=7.9 Hz, 1H); 7.23(d, J=8.2 Hz, 2H); 7.33 (d, J=8.2 Hz, 2H).

[0323] The brown oil (1.05 g, 1.9 mmol) was dissolved in 8 mL ofacetonitrile with 0.53 g (2.9 mmol) of tetraethylammonium fluoridedihydrate and stirred for 30 minutes at room temperature. Afterevaporation of solvent, the residue was redissolved in 1N hydrochloricacid and diethyl ether. The aqueous phase was separated and neutralizedto pH 8 with 1N sodium hydroxide solution. The product was extractedusing dichloromethane and washed with brine. The organic phase was driedover sodium sulfate and the solvent removed to give 0.69 g of(−)-4-((αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.

[0324] NMR (300 MHz, DMSO-d₆): δ 0.95 (d, J=5.4 Hz, 3H); 1.00 (d, J=5.4Hz, 3H); 1.13 (br s, 6H); 2.19 (app t, J=10.0 Hz, 1H); 2.26-2.41 (m,3H); 2.55 (m, partially obscured by DMSO, 1H); 2.81 (dd, J₁=7.9 Hz,J₂=14.1 Hz, 1H); 2.89 (br d, J=6.2 Hz, 1H); 3.21 (br s, 2H); 3.21 (m,obscured, 1H); 3.39 (br s, 2H); 4.54 (s, 1H); 5.17 (d, J=11.3 Hz, 1H),5.22 (d, J=19.6 Hz, 1H); 5.82-5.96 (m, 1H); 6.60 (d, J=7.8 Hz, 1H); 6.93(m, 2H); 7.11 (t, J=7.9 Hz, 1H); 7.31 (d, J=7.9 Hz, 2H); 7.52 (d, J=7.9Hz, 2H); 9.39 (s, 1H).

[0325] Mass spectrum (CI-CH₄) m/z: 436 (M+1.12%), 282 (100%), 153 (3%).[α]_(D) ²⁰=27.8° (ethanol, c=1.2).

[0326] A portion of the free amine (0.100 g) was dissolved in ethanoland titrated with ethanolic hydrogen chloride to pH 4.0, followed byprecipitation with diethyl ether from dichloromethane to give 0.089 g ofthe monohydrochloride salt as a hygroscopic beige powder. Calculationsfor C₂₇H₃₇N₃O₂ HCl 0.75H₂O: C, 66.78, H, 8.20; N, 8.65 Cl, 7.30. Found:C, 66.90; H, 8.05; N, 8.69; Cl, 7.13.

EXAMPLE 19

[0327](−)-4-((αS)-α-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide

[0328] The first isomer to elute from the column of Example 1 wasobtained as 1.39 g of a brown oil.

[0329] NMR (300 MHz, DMSO-d₆): δ 0.11 (s, 6H); 0.86 (d, J=6.8 Hz, 3H);0.88 (m,9H); 0.94 (d, J=6.8 Hz, 3H); 1.02 (br s, 6H); 2.14 (app t,J=10.7 Hz, 1H); 2.25-2.38 (m, 3H); 2.55 (dd, partially obscured by DMSO,1H); 2.73 (dd, J₁=7.4 Hz, J₂=13.9 Hz, 1H); 2.84 (br s, 1H); 3.13 (br s,2H); 3.28 (m, obscured by water, 1H); 3.34 (br s, 2H); 4.55 (s, 1H);5.09 (d, J=11.3 Hz, 1H), 5.14 (d, J=19.9 Hz, 1H); 5.74-5.84 (m, 1H);6.63 (d, J=7.8 Hz, 1H); 6.90 (s, 1H); 7.02 (d, J=7.6 Hz, 1H); 7.13 (t,J=7.8 Hz, 1H); 7.23 (d, J=8.1 Hz, 2H); 7.47 (d, J=8.1 Hz, 2H).

[0330] The brown oil (0.95 g, 1.73 mmol) was dissolved in 8 mL ofacetonitrile with 0.48 g (2.6 mmol) of tetraethylammonium fluoridedihydrate and stirred for 30 minutes at room temperature. Afterevaporation of solvent, the residue was redissolved in 1N hydrochloricacid and diethyl ether. The aqueous phase was separated and neutralizedto pH 8 with 1N sodium hydroxide solution. The product was extractedusing dichloromethane, then washed with brine. The organic phase wasdried over sodium sulfate and the solvent removed to give 0.64 g. of(−)-4-((α)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.

[0331] NMR (300 MHz, DMSO-d₆): δ 0.89 (d, J=5.8 Hz, 3H); 0.98 (d, J=5.8Hz, 3H); 1.08 (br s, 6H); 2.10-2.43 (m, 4H); 2.56 (m, partially obscuredby DMSO, 1H); 2.78 (dd, J₁=7.7 Hz, J₂=14.4 Hz, 1H); 2.97 (br d, J=6.0Hz, 1H); 3.17-3.43 (m, 5H); 4.51 (s, 1H); 5.13 (d, J=8.6 Hz, 1H), 5.19(d, J=15.6 Hz, 1H); 5.75-5.88 (m, 1H); 6.57 (d, J=6.8 Hz, 1H); 6.88 (m,2H); 7.04 (t, J=7.7 Hz, 1H); 7.27 (d, J=8.0 Hz, 2H); 7.50 (d, J=8.0 Hz,2H); 9.34 (s, 1H). Mass spectrum (CI-CH4) m/z: 436 (M+1, 23%), 282(100%), 153 (4%). [α]_(D) ²⁰=−27.3° (ethanol, c=1.2).

[0332] A portion of the free amine (0.100 g) was dissolved in ethanoland titrated with ethanolic hydrogen chloride to pH 4.0, followed byprecipitation with diethyl ether from dichloromethane to give 0.075 g ofthe monohydrochloride salt as a hygroscopic off-white powder.Calculations for C₂₇H₃₇N₃O₂ HCl 0.5H₂O: C, 67.41, H, 8.17; N, 8.73 Cl,7.37. Found: C, 67.16; H, 8.18; N, 8.81; Cl, 7.26.

EXAMPLE 20

[0333](−)-4-((αR)-α-((2R,5R)-2,5-Dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

[0334](−)-4-((αR)-α-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(0.075 g, 0.17 mmol, Example 1) was dissolved in toluene (10 mL), addedto a 3-neck flask containing Lindlar's catalyst (0.071 g, ca. 0.033 mmolPd) and stirred for 3.5 hours under a hydrogen atmosphere. The solutionwas filtered through celite, the solvent was evaporated under vacuum,and the residue was purified on silica gel with 5% ethanol indichloromethane to give 0.065 g. of(−)-4-((αR)-α-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamideas a light-brown solid.

[0335] NMR (300 MHz, DMSO-d₆): δ 0.75-1.41 (m, 17H); 2.10-2.43 (m, 4H);2.56 (m, partially obscured by DMSO, 1H); 2.87 (m, 1H); 3.03-3.52 (m,6H); 4.50 (s, 1H); 6.57 (d, J=7.4 Hz, 1H); 6.91 (m, 2H); 7.07 (t, J=7.9Hz, 1H); 7.27 (d, J=7.7 Hz, 2H); 7.48 (d, J=7.7 Hz, 2H); 9.33 (s, 1H).Mass spectrum (C₁-CH4) m/z: 438 (M+1, 5%), 282 (100%), 155 (4%). [α]_(D)²⁰=−37.5° (ethanol, c=1.2).

[0336] A portion of the free amine (0.055 g) was dissolved in ethanoland titrated with ethanolic hydrogen chloride to pH 4.0, followed byprecipitation with diethyl ether from dichloromethane to give 0.045 g ofthe monohydrochloride salt as a hygroscopic beige powder. Calculationsfor C₂₇H₃₉N₃O₂ HCl 0.5H₂O: C, 67.13, H, 8.55; N, 8.70. Found: C, 67.23;H, 8.55; N, 8.49.

EXAMPLE 21

[0337](−)-4-((αS)-α-((2R,5R)-2,5-Dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

[0338] (−)-4-((αS)-α-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(0.200 g, 0.46 mmol, Example 2) was dissolved in toluene (10 mL) andstirred for 4 hours under a hydrogen atmosphere. The solution wasfiltered through celite to give 0.182 g of crude product. The phenol wasreprotected as follows to improve chromatographic resolution. A mixtureof crude product (0.18 g), tert-butylchlorodimethylsilane (0.93 g), andimidazole (0.070 g) in 10 mL of acetonitrile was stirred overnight atroom temperature. The reaction solution was poured into 100 mL of waterand extracted with two 50 mL portions of dichloromethane. The combinedextracts were dried over sodium sulfate and the solvent removed. Theresidue was purified on a column of silica gel with ethanol (0-4%) indichloromethane to give 0.085 g of 4-((αS)-α-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamideas a light-brown solid.

[0339] The material (0.080 g) was dissolved in acetonitrile (5 mL) andtreated with tetraethylammonium fluoride dihydrate (0.040 g). After 30minutes the solvent was removed under reduced pressure. The residue wasdissolved in 1N hydrochloric acid (5 mL) and washed two times withdiethyl ether. The aqueous phase was then adjusted to pH 9 with 1Nsodium hydroxide solution and extracted with dichloromethane. Thedichloromethane extracts were combined, dried over sodium sulfate, andthe solvent removed under reduced pressure to give 0.056 g of(−)-4-((αS)-α-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamideas a light-brown solid.

[0340] NMR (300 MHz, DMSO-d₆): δ 0.72-1.41 (m, 17H); 1.95-2.34 (m, 4H);2.56 (m, partially obscured by DMSO, 1H); 2.91 (m, 1H); 3.02-3.48 (m,6H); 4.47 (s, 1H); 6.56 (br s, 1H); 6.83 (m, 2H); 7.05 (m, 1H); 7.24 (d,J=6.5 Hz, 2H); 7.46 (d, J=6.5 Hz, 2H); 9.31 (s, 1H). Mass spectrum(C₁-CH₄) m/z: 438 (M+1, 12%), 282 (100%), 155 (4%). [α]_(D) ²⁰=36.70(ethanol, c=1.3).

[0341] The free amine (0.044 g) was dissolved in ethanol and titratedwith ethanolic hydrogen chloride to pH 4.0, followed by precipitationwith diethyl ether from dichloromethane to give 0.031 g of themonohydrochloride salt as a hygroscopic off-white powder. Calculationsfor C₂₇H₃₉N₃O₂ HCl H₂O: C, 65.90, H, 8.60; N, 8.54 Found: C, 65.72; H,8.41; N, 8.52.

EXAMPLE 22

[0342]4-((αR)-α-(2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-benzamide

[0343] 3-Bromophenoxy-tert-butyldimethylsilane (146 g, 0.51 mol, Example1, infra) was dissolved in dry tetrahydrofuran under nitrogen and cooledto −78° C. A solution of 1.6 M n-butyllithium in hexane (318 mL, 0.51mol) was added dropwise at a rate to maintain temperature below −70° C.The reaction was stirred for 30 minutes after the addition was complete,and the cold solution was transferred to another vessel containing acold (−78° C.) solution of 4-bromobenzaldehyde (94.3 g, 0.51 mol) in1000 mL of dry tetrahydrofuran under nitrogen. The transfer rate wasmonitored to maintain reaction temperature below −70° C. The reactionmixture was stirred for another 45 minutes at −78° C. and then quenchedwith 100 mL of saturated aqueous ammonium chloride. After warming toroom temperature, the mixture was diluted with 2000 mL of diethyl etherand washed with 2000 mL of water followed by 500 mL of saturated sodiumchloride. The ethereal solution was dried over sodium sulfate and thesolvent removed to give 197.2 g of crudeα-(4-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl alcohol as ayellow oil.

[0344] NMR (200 MHz, CDCl₃): δ 0.2 (s, 6H); 0.9 (s, 6H); 5.7 (s, 1H);6.75 (dd, J₁=2 Hz, J₂=8 Hz, 1H); 6.8 (br s, 1H); 6.9 (d, J=8 Hz, 1H);7.15 (t, J=8 Hz, 1H); 7.25 and 7.45 (AB q, J=8 Hz, 4H).

[0345] The crude benzhydryl alcohol (53.2 g, 135 mmol) was dissolved in1000 mL of dichloromethane and 14.7 mL (202 mmol) of thionyl chloridewas added dropwise. The solution was stirred overnight at roomtemperature and the solvent was removed under vacuum. The crude productwas redissolved in 500 mL of toluene and the solvent again was removedunder vacuum to eliminate excess thionyl chloride, providing crudeα-(4-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl chloride as adark oil.

[0346] NMR (200 MHz, CDCl₃): δ 0.2 (s, 6H); 1.0 (s, 9H); 6.0 (s, 1H);6.78 (dd, J₁=1 Hz, J₂=8 Hz, 1H); 6.9 (m, 2H); 7.2 (t, J=8 Hz, 2H); 7.27and 7.47 (AB q, J=8 Hz, 4H).

[0347] The crude benzhydryl chloride (approx. 42 mmol) was combined with9.55 g (84 mmol) of (+)-(2S,5S)-2,5-dimethylpiperazine, prepared fromL-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pa.) asdescribed in J. Org. Chem. 50: 4909-13 (1985), and 30 mL of toluene andheated at reflux overnight under nitrogen. The toluene was removed undervacuum, and the residue was redissolved in diethyl ether and washed with1.0 M sodium hydroxide followed by saturated aqueous sodium chloride.The ether solution was dried over sodium sulfate and the solvent removedto give a dark oil. The product was purified by chromatography on silicagel (Waters Prep 500) with 0.5-0.7% ethanol in dichloromethane with 0.1%triethylamine to give 8.01 g (39%) of(2S,5S)-1-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazineas a 1:1 mixture of diastereomers.

[0348] The purified benzhydrylpiperazine (1.51 g, 3.1 mmol) wasdissolved in 20 mL of dry tetrahydrofuran with 0.27 mL (3.2 mmol) ofallyl bromide and 1.6 g (15.5 mmol) of sodium carbonate and heated atreflux overnight under nitrogen. The cooled reaction solution wasfiltered and the solvent removed to give 1.62 g of crude(2S,5S)-1-allyl-4-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazineas a yellow oil.

[0349] NMR (200 MHz, CDCl₃): δ 0.15 (s, 6H); 0.95-1.1 (m, 12H); 1.45 (m,1H); 2.2-2.55 (m, 4H); 2.6 (m, 1H); 2.75-3.1 (m, 2H); 3.4 (m, 1H); 4.45(s, 1H); 5.1-5.25 (m, 3H); 5.85 (m, 1H); 6.75 (d, J=8 Hz, 1H); 6.8-6.95(m, 2H); 7.1 (m, 1H); 7.2-7.5 (m, 4H).

[0350] The product from above (1.40 g, 2.6 mmol) was dissolved in 10 mLof dry tetrahydrofuran and cooled to −78° C. under nitrogen. A solutionof 1.6 M n-butyllithium in hexane (1.6 mL, 2.6 mmol) was added dropwiseat a rate to maintain temperature below −70° C. After the orangesolution was stirred an additional 30 minutes at low temperature,anhydrous carbon dioxide gas was introduced into the reaction solutionat a rate to maintain temperature below −60° C. Carbon dioxide additionwas stopped when the color of the reaction solution became a paleyellow. The reaction was allowed to warm to room temperature withstirring and the solvent was removed under vacuum. The residue wasredissolved in 50 mL of toluene and the solvent again removed undervacuum in order to eliminate residual n-bromobutane. The reactionprovided 1.39 g of the lithium salt of4-((αR)-α-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoicacid.

[0351] The lithium benzoate salt (1.39 g, 2.8 mmol) was dissolved indichloromethane and cooled to 0° C. Thionyl chloride (0.3 mL, 4.2 mmol)was added dropwise. After stirring for two hours at 0° C. concentratedammonium hydroxide (6.0 mL) was added. The resulting dark yellow slurrywas allowed to warm to room temperature and stirred for another hour.The reaction solution was washed with water and dried over sodiumsulfate. After removal of the solvent, the residue was purified bychromatography on silica gel with 1-3% methanol in dichloromethane togive 0.10 g of4-((αR)-α-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzamideas a yellow resin.

[0352] NMR (200 MHz, CDCl₃): δ 0.15 (s, 6H); 0.95 (s, 9H); 0.97 (d, J=6Hz, 3H); 1.05 (d, J=6 Hz, 3H); 2.2-2.5 (m, 4H); 2.65 (m, 1H); 2.8 (m,1H); 3.0 (m, 1H); 3.5 (m, 1H); 4.55 (s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2(d, J=16 Hz, 1H); 5.85 (m, 1H); 6.1 (br s, 2H); 6.65 (d, J=8 Hz, 1H);6.9 (s, 1H); 6.95 (d, J=8 Hz, 1H); 7.1 (t, J=8 Hz, 1H); 7.55 and 7.7 (ABq, J=8 Hz, 4H).

[0353] The benzamide from above (0.10 g, 0.20 mmol) was dissolved in 2mL of acetonitrile with 60 mg (0.3 mmol) of tetraethylammonium fluoridehydrate and stirred for 1 hour at room temperature. After evaporation ofthe solvent, the residue was redissolved in dichloromethane and washedwith water (pH=8), then dried over sodium sulfate and the solventremoved to give 90 mg of a beige solid. The monohydrochloride salt wasprepared by titration to pH 4.3 with ethanolic hydrogen chloride(approximately 0.2 M) followed by precipitation with diethyl ether togive 49 mg of4-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxy-benzyl)benzamidehydrochloride as a hygroscopic white powder. Calculations for C₂₃H₂₉N₃O₂HCl 1.5H₂O: C, 62.36; H, 7.51; N, 9.49; Cl, 8.00. Found: C, 62.38; H,7.42; N, 9.41; Cl, 8.10. Mass spec (C₁-CH₄): m/z 380 (M+1, 100%)

EXAMPLE 23

[0354](−)-3-((S)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol

[0355] A solution of 3-bromophenol (500 g, 2.89 mol),tert-butylchlorodimethylsilane (436 g, 2.89 mol), and imidazole (500 g,7.22 mol) in 500 mL of dimethylformamide was stirred overnight at roomtemperature. The reaction solution was poured into 3000 mL of water andextracted with two 2000 mL portions of diethyl ether. The combined etherextracts were dried over sodium sulfate and the solvent removed to give846 g of 3-(bromophenoxy)-tert-butyldimethylsilane as a pale yellowliquid. NMR (300 MHz, CDCl₃): δ 0.2 (s,6H); 1.0 (s,9H); 6.75 (m,1H); 7.0(br s, 1H); 7.1 (m,2H).

[0356] A 12 L, 3-necked round bottom flask was charged withtrans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had beenrecrystallized from toluene to mp=115-119° C., and 600 mL of water. Theflask was cooled in an ice bath and a solution of methanesulfonic acid(1290 g, 13.4 mol) in 600 mL of water was added slowly with stirring andcooling to maintain the temperature below 40° C. The solution was cooledto 20° C. and 800 mL of ethanol was added. A 500 mL addition funnel wasfilled with 60% aqueous potassium acetate from a 2 L reservoir of thesolution, and potassium acetate was added to the reaction flask toadjust the pH to 4.0. A second addition funnel was charged with asolution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL oftetrahydrofuran. The ethyl chloroformate and potassium acetate solutionswere simultaneously added dropwise with adjustment of rate to maintainthe reaction solution at pH 4.0±0.1, with cooling as necessary tomaintain temperature at 25° C. After addition of the ethyl chloroformatewas complete, the reaction was stirred for 1 hour with continuedaddition of potassium acetate solution to maintain a pH of 4.0. Theorganic solvents were removed by distillation under vacuum. Theremaining aqueous solution was washed with 1500 mL of ethyl acetate toremove any bis-carbamate impurity. The ethyl acetate wash was extractedwith two 500 mL portions of 1M hydrochloric acid to recover desiredproduct. The acid extracts were combined with the original aqueoussolution and the pH was adjusted to 11 by addition of 10 M sodiumhydroxide, with cooling to maintain temperature below 40 C. The aqueoussolution was extracted with two 1500 mL portions of ethyl acetate, thecombined extracts were dried over magnesium sulfate, and the solvent wasremoved to give 927 g (74%) ethyltrans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.

[0357] A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate(643 g, 3.45 mol), allyl bromide (328 mL, 3.80 mol), and sodiumcarbonate (440 g, 4.15 mol) in 2500 mL of acetonitrile was heated atreflux for 1.5 hours. The reaction was cooled to room temperature,filtered, and the solvent removed under vacuum. The residue wasdissolved in 4000 mL of dichloromethane and washed with two 500 mLportions of 1 M sodium hydroxide. The dichloromethane solution was driedover magnesium sulfate and the solvent was removed to give 630 g (81%)of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.

[0358] Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g,2.78 mol) was added to a solution of 87% potassium hydroxide pellets(2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5hours. Carbon dioxide evolution was observed for the first 0.5 l hour ofheating. The reaction was cooled below reflux temperature and 2000 mL oftoluene was carefully added. Ethanol was removed by azeotropicdistillation at 105 C, while adding an additional 4000 mL of toluene tothe reaction flask during the course of the distillation. Aftercollection of 9000 mL of distillate, the reaction was cooled to 100 Cand 1000 mL of toluene was carefully added. The solution was slowlycooled to 5 C and maintained at 5 C for 30 minutes. The solution wasfiltered, and the filter cake was washed with an additional 1500 mL oftoluene. The filtrate was washed with 1000 mL of water, dried overmagnesium sulfate, and the solvent was removed to give 296 g (69%) oftrans-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz,DMSO-d₆): δ 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t,J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33(dd, J₁=5 Hz, J₂=14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz,1H) 5.8 (m, 1H).

[0359] Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., SouthPlainfield, N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot (˜60° C.) 95%ethanol (16 L) and racemic trans-1-allyl-2,5-dimethylpiperazine (500 g,3.2 mol) was added in several portions (caution: exothermic). The hotsolution was seeded with crystals of the diastereoisomerically pure salt(obtained from a previous small-scale resolution) and cooled to roomtemperature over 2-3 hours. The solution was slowly stirred for 2 daysat room temperature. The resulting salt was collected by filtration,washed twice with 95% ethanol, and dried under vacuum to give 826.5 g ofa white solid (47%). The process was repeated with a second batch of thedi-p-toluoyl-D-tartaric acid and racemictrans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).

[0360] The total of 1695 g of salt was divided into three batches andeach batch was recrystallized twice in the following fashion. The saltwas dissolved in refluxing 95% ethanol (˜2.7 L/100 g of salt), andapproximately half of the ethanol was removed by distillation. (Note:vigorous stirring was necessary during distillation to preventcrystallization on the vessel wall.) The hot solution was seeded withcrystals of the pure diastereomeric salt, cooled to room temperature,and stirred slowly for 2 days before collecting the salt by filtration.(Note: a subsequent experiment suggested that crystallization time canbe reduced from 2 days to 8 hours.) The total amount recovered was 1151g. The salt was dissolved in 3 L of 2 M aqueous sodium hydroxide, andthe aqueous solution was extracted with four 1 L portions ofdichloromethane. The organic extracts were combined, dried over sodiumsulfate, and solvent removed by rotary evaporation (temperature <20° C.)to give 293 g (29% based on 20 racemic weight) of(2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil. [α]_(D) ²⁰=−55.1(abs. ethanol, c=1.2). The trifluoroacetamide of the product wasprepared with trifluoroacetic anhydride and analyzed by chiral capillarygas chromatography (Chiraldex B-PH column, 20 m×0.32 mm, AdvancedSeparation Technologies Inc., Whippany, N.J., 120° C.) indicating anenantiopurity of >99% ee (retention time of desired enantiomer, 11.7min; other enantiomer, 10.7 min).

[0361] 3-Phenoxy-tert-butyldimethylsilane magnesium bromide was formedby the slow addition of 2.7 M n-butyllithium in heptane (150 mL, 405mmol) to a solution of 3-bromophenoxy-tert-butyldimethylsilane (123.44g, 429 mmol) in 500 mL anhydrous tetrahydrofuran at −70° C. Afterstirring 45 min. this cold solution was siphoned under nitrogen into aslurry of magnesium bromide etherate (110.62 g, 428 mmol) in 650 mLanhydrous tetrahydrofuran at room temperature, and stirred for 45 min.

[0362] Thiophene-3-carboxaldehyde (29.09 g, 259 mmol), benzotriazole(30.91 g, 259 mmol), and (2R,5S)-1-allyl-2,5-trans-dimethylpiperazine(40.01 g, 259 mmol) were dissolved in 250 mL toluene and heated to agentle reflux. The water-toluene azeotrope was collected in a Dean-Starktrap over the course of 2.5 hours. The remaining solvent was removedunder vacuum. The residue was dissolved in 150 mL anhydroustetrahydrofuran and added to a solution of3-phenoxy-tert-butyldimethylsilane magnesium bromide in anhydroustetrahydrofuran (1150 mL, 0.35 M) under a nitrogen atmosphere.

[0363] The reaction was stirred at room temperature for 2 hours and thenquenched by the addition of 25 mL saturated NH₄Cl solution. Anhydrousmagnesium sulfate (˜5 g) and Celite (˜10 g) were added. The mixture wasstirred and filtered, and the solvent was removed under reducedpressure. The residue was dissolved in ethyl acetate and washed firstwith 0.5 N NaOH solution (5×200 mL) and then with brine (1×200 mL). Thesolution was dried (Na₂SO₄/MgSO₄) and concentrated under reducedpressure.

[0364] The dark residue was dissolved in 250 mL anhydrous acetonitrileand tetraethyl-ammonium fluoride dihydrate (72.26 g, 390 mmol) wasadded. After stirring for 90 min. the reaction was concentrated and theresidue was dissolved in 200 mL ethyl acetate. The mixture was extractedwith dilute NaHCO₃ solution (3×200 mL) and with water (1×200 mL). Theorganic layer was diluted with 200 mL diethyl ether and extracted with10% citric acid solution (8×200 mL). The combined aqueous extracts wasadjusted to pH 8.5 using 50% NaOH solution and extracted withdichloromethane (3×200 mL). The solution was dried (Na₂SO₄/MgSO₄) andconcentrated under reduced pressure. The resulting tan solid (53.25 g,155 mmol) was crystallized twice from 225 mL of 2:1/isopropanol: waterto yield fluffy, white needle crystals (34.14 g, 99.7 mmol), [α]=_(D)²⁰8.33° (abs. ethanol, c=1.0).

[0365]¹H NMR (500 MHz, d₆-DMSO): δ9.32 (s, 1H), 7.44 (dd, J=3.2, 4.9 Hz,1H), 7.15 (s,1H), 7.13 (t, J=8.25 Hz, 1H), 6.98 (d, J=4.9 Hz, 1H),6.66-6.70 (m, 3H), 5.73-5.81 (m, 1H), 5.15 (d, J=17.1 Hz, 1H), 5.09 (d,J=10.5 Hz, 1H), 5.02 (s,1H), 3.20 (br d, J=10.2 Hz, 1H), 2.78 (dd,J=7.3, 7.5 Hz, 1H), 2.68 (dd, J=2.6, 11.3 Hz, 1H), 2.59 (dd, J=1, 9.3Hz, 1H), 2.44 (br s, 2H), 2.02 (t, J=8.6 Hz, 1H), 1.81 (t, J=8.1 Hz,1H), 1.09 (d, J=6 Hz, 3H), 0.91 (d, J=6 Hz, 3H).

[0366] Calculated for C₂₀H₂₆N₂OS: C, 70.14; H, 7.65; N, 8.18; S, 9.36%.

[0367] Found: C,70.19; H, 7.58; N, 8.12; S, 9.33%.

EXAMPLE 24

[0368]3-((S)-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol

[0369] A solution of 3-bromophenol (500 g, 2.89 mol),tert.-butylchlorodimethylsilane (436 g, 2.89 mol), and imidazole (500 g,7.22 mol) in 500 mL of dimethylformamide was stirred overnight at roomtemperature. The reaction solution was poured into 3000 mL of water andextracted with two 2000 mL portions of diethyl ether. The combinedeither extracts were dried over sodium sulfate and the solvent removedto give 846 g of 3-(bromophenoxy)-tert.-butyldimethylsilane as a paleyellow liquid. NMR (300 MHz, CDCl₃): δ 0.2 (s,6H); 1.0 (s,9H); 6.75(m,1H); 7.0 (br s, 1H); 7.1 (m,2H).

[0370] A 12 L, 3-necked round bottom flask was charged withtrans-2,5-dimethylpiperazine (767 g, 6.72 mol), which had beenrecrystallized from toluene to mp=115-119° C., and 600 mL of water. Theflask was cooled in an ice bath and a solution of methanesulfonic acid(1290 g, 13.4 mol) in 600 mL of water was added slowly with stirring andcooling to maintain the temperature below 40° C. The solution was cooledto 20° C. and 800 mL of ethanol was added. A 500 mL addition funnel wasfilled with 60% aqueous potassium acetate from a 2 L reservoir of thesolution, and potassium acetate was added to the reaction flask toadjust the pH to 4.0. A second addition funnel was charged with asolution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL oftetrahydrofuran. The ethyl chloroformate and potassium acetate solutionswere simultaneously added dropwise with adjustment of rate to maintainthe reaction solution at pH 4.0±0.1, with cooling as necessary tomaintain temperature at 25° C. After addition of the ethyl chloroformatewas complete, the reaction was stirred for 1 hour with continuedaddition of potassium acetate solution to maintain a pH of 4.0. Theorganic solvents were removed by distillation under vacuum. Theremaining aqueous solution was washed with 1500 mL of ethyl acetate toremove any bis-carbamate impurity. The ethyl acetate wash was extractedwith two 500 mL portions of 1 M hydrochloric acid to recover desiredproduct. The acid extracts were combined with the original aqueoussolution and the pH was adjusted to 11 by addition of 10 M sodiumhydroxide, with cooling to maintain temperature below 40° C. The aqueoussolution was extracted with two 1500 mL portions of ethyl acetate, thecombined extracts were dried over magnesium sulfate, and the solvent wasremoved to give 927 g (74%) ethyltrans-2,5-dimethyl-1-piperazinecarboxylate as a yellow oil.

[0371] A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate(643 g, 3.45 mol), allyl bromide (328 mL, 3.80 mol), and sodiumcarbonate (440 g, 4.15 mol) in 2500 mL of acetonitrile was heated atreflux for 1.5 hours. The reaction was cooled to room temperature,filtered, and the solvent removed under vacuum. The residue wasdissolved in 4000 mL of dichloromethane and washed with two 500 mLportions of 1 M sodium hydroxide. The dichloromethane solution was driedover magnesium sulfate and the solvent was removed to give 630 g (81%)of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.

[0372] Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g,2.78 mol) was added to a solution of 87% potassium hydroxide pellets(2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5hours. Carbon dioxide evolution was observed for the first 0.5-1 hour ofheating. The reaction was cooled below reflux temperature and 2000 mL oftoluene was carefully added. Ethanol was removed by azeotropicdistillation at 105° C., while adding an additional 4000 mL of tolueneto the reaction flask during the course of the distillation. Aftercollection of 9000 mL of distillate, the reaction was cooled to 100° C.and 1000 mL of toluene was carefully added. The solution was slowlycooled to 5° C. and maintained at 5° C. for 30 minutes. The solution wasfiltered, and the filter cake was washed with an additional 1500 mL oftoluene. The filtrate was washed with 1000 mL of water, dried overmagnesium sulfate, and the solvent was removed to give 296 g (69%) oftrans-1-allyl-2,5-dimethylpiperazine as a dark liquid. NMR (300 MHz,DMSO-d₆): δ 0.87 (d, J=6.3 Hz, 3H); 0.92 (d, J=6.3 Hz, 3H); 1.63 (t,J=11 Hz, 1H); 2.05 (m, 1H); 2.30 (t, J=11 Hz, 1H); 2.6-2.8 (m, 4H); 3.33(dd, J₁=5 Hz, J₂=14 Hz, 1H); 5.09 (d, J=8.7 Hz, 1H); 5.13 (d, J=14 Hz,1H) 5.8 (m, 1H).

[0373] Di-p-toluoyl-D-tartaric acid (Schweizerhall, Inc., SouthPlainfield, N.J.) (1.25 Kg, 3.2 mol) was dissolved in hot (˜60° C.) 95%ethanol (16 L) and racemic trans-1-allyl-2,5-dimethylpiperazine (500 g,3.2 mol) was added in several portions (caution: exothermic). The hotsolution was seeded with crystals of the diastereoisomerically pure salt(obtained from a previous small-scale resolution) and cooled to roomtemperature over 2-3 hours. The solution was slowly stirred for 2 daysat room temperature. The resulting salt was collected by filtration,washed twice with 95% ethanol, and dried under vacuum to give 826.5 g ofa white solid (47%). The process was repeated with a second batch of thedi-p-toluoyl-D-tartaric acid and racemictrans-1-allyl-2,5-dimethylpiperazine to give 869 g (50%).

[0374] The total of 1695 g of salt was divided into three batches andeach batch was recrystallized twice in the following fashion. The saltwas dissolved in refluxing 95% ethanol (˜2.7 L/100 g of salt), andapproximately half of the ethanol was removed by distillation. (Note:vigorous stirring was necessary during distillation to preventcrystallization on the vessel wall.) The hot solution was seeded withcrystals of the pure diastereomeric salt, cooled to room temperature,and stirred slowly for 2 days before collecting the salt by filtration.(Note: a subsequent experiment suggested that crystallization time canbe reduced from 2 days to 8 hours.) The total amount recovered was 1151g. The salt was dissolved in 3 L of 2 M aqueous sodium hydroxide, andthe aqueous solution was extracted with four 1 L portions ofdichloromethane. The organic extracts were combined, dried over sodiumsulfate, and solvent removed by rotary evaporation (temperature <20° C.)to give 293 g (29% based on racemic weight) of(2R,5S)-1-allyl-2,5-dimethylpiperazine as a clear oil. [α_(D) ²⁰]=−55.1(abs. ethanol, c=1.2). The trifluoroacetamide of the product wasprepared with trifluoroacetic anhydride and analyzed by chiral capillarygas chromatography (Chiraldex B-PH column, 20 m×0.32 mm, AdvancedSeparation Technologies Inc., Whippany, N.J., 120° C.) indicating anenantiopurity of >99% ee (retention time of desired enantiomer, 11.7min; other enantiomer, 10.7 min).

[0375] 3-Phenoxy-tert-butyldimethylsilane magnesium bromide was formedby the slow addition of 2.7 M n-butyllithium in heptane (150 mL, 405mmol) to a solution of 3-bromophenoxy-tert-butyldimethylsilane (123.44g, 429 mmol) in 500 mL anhydrous tetrahydrofuran at −70° C. Afterstirring 45 min. this cold solution was siphoned under nitrogen into aslurry of magnesium bromide etherate (110.62 g, 428 mmol) in 650 mLanhydrous tetrahydrofuran at room temperature, and stirred for 45 min.

[0376] Thiophene-3-carboxaldehyde (29.09 g, 259 mmol), benzotriazole(30.91 g, 259 mmol), and (2R,5S)-1-allyl-2,5-trans-dimethylpiperazine(40.01 g, 259 mmol) were dissolved in 250 mL toluene and heated to agentle reflux. The water-toluene azeotrope was collected in a Dean-Starktrap over the course of 2.5 hours. The remaining solvent was removedunder vacuum. The residue was dissolved in 150 mL anhydroustetrahydrofuran and added to a solution of3-phenoxy-tert-butyldimethylsilane magnesium bromide in anhydroustetrahydrofuran (1150 mL, 0.35 M) under a nitrogen atmosphere.

[0377] The reaction was stirred at room temperature for 2 hours and thenquenched by the addition of 25 mL saturated NH₄Cl solution. Anhydrousmagnesium sulfate (˜5 g) and Celite (˜10 g) were added. The mixture wasstirred and filtered, and the solvent was removed under reducedpressure. The residue was dissolved in ethyl acetate and washed firstwith 0.5 N NaOH solution (5×200 mL) and then with brine (1×200 mL). Thesolution was dried (Na₂SO₄/MgSO₄) and concentrated under reducedpressure.

[0378] The dark residue was dissolved in 250 mL anhydrous acetonitrileand tetraethyl-ammonium fluoride dihydrate (72.26 g, 390 mmol) wasadded. After stirring for 90 min. the reaction was concentrated and theresidue was dissolved in 200 mL ethyl acetate. The mixture was extractedwith dilute NaHCO₃ solution (3×200 mL) and with water (1×200 mL). Theorganic layer was diluted with 200 mL diethyl ether and extracted with10% citric acid solution (8×200 mL). The combined aqueous extracts wasadjusted to pH 8.5 using 50% NaOH solution and extracted withdichloromethane (3×200 mL). The solution was dried (Na₂SO₄/MgSO₄) andconcentrated under reduced pressure. The resulting tan solid (53.25 g,155 mmol) was crystallized twice from 225 mL of 2:1/isopropanol: waterto yield fluffy, white needle crystals (34.14 g, 99.7 mmol) of3-((S)-((2S,SR)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol.

[0379]¹H NMR (500 MHz, d₆-DMSO): δ 9.32 (s, 1H), 7.44 (dd, J=3.2, 4.9Hz,1H), 7.15 (s,1H), 7.13 (t, J=8.25 Hz, 1H), 6.98 (d, J=4.9 Hz, 1H),6.66-6.70 (m, 3H), 5.73-5.81 (m, 1 H), 5.15 (d, J=17.1 Hz, 1H), 5.09 (d,J=10.5 Hz, 1H), 5.02 (s,1H), 3.20 (br d, J=10.2 Hz,1H), 2.78 (dd, J=7.3,7.5 Hz, 1H), 2.68 (dd, J=2.6, 11.3 Hz, 1H), 2.59 (dd, J=1, 9.3 Hz,1H),2.44 (br s, 2H), 2.02 (t, J=8.6 Hz,1H), 1.81 (t, J=8.1 Hz, 1H), 1.09 (d,J=6 Hz, 3H), 0.91 (d, J=6 Hz, 3H). Calculated for C₂₀H₂₆N₂OS: C, 70.14;H, 7.65; N, 8.18; S, 9.36%. Found: C70.19; H, 7.58; N, 8.12; S, 9.33%.

[0380]3-((S)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol(8.56 g, 25 mmol), N-phenyltrifluoromethanesulfonimide (9.86 g, 27.6mmol), and triethylamine (8.0 mL, 57.1 mmol) were dissolved in 75 mLdichloromethane and stirred overnight at room temperature undernitrogen. After concentrating under reduced pressure, the residue wasdissolved in 150 mL ethyl acetate and washed with Na₂CO₃ solution (3×150mL), water (1×100 mL), and brine (1×100 mL). The solution was dried(Na₂SO₄/MgSO₄) and concentrated under reduced pressure. The residual oilwas purified by chromatography on silica gel (2% NH₄OH in EtOAc/CH₂Cl₂)to give 11.8 g (24.8 mmol) of a viscous, light yellow oil.

[0381] The allyl portion was removed using Pd(dba)₂/DPPB in the presenceof thiosalicylic acid by the method of Genet [J.P. Genet, S.Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270(1995)]. The reaction was concentrated and the residue was dissolved in50 mL ethyl acetate and 100 mL diethyl ether. After washing this withNa₂CO₃ solution (3×150 mL) and water (1×100 mL), the organic solutionwas extracted with 3 N HCl (2×20 mL) and 1 N HCl (2×20 mL). The acidicextract was adjusted to pH 8.5 using NaOH solution and extracted withdichloromethane (3×50 mL). The solution was dried (Na₂SO₄/MgSO₄) andconcentrated under reduced pressure. The residual oil was purified bychromatography on silica gel (2% NH₄OH in EtOAc/CH₂Cl₂) to give 8.83 g(20.3 mmol) of a viscous, light amber oil.

[0382] The above free amine (1.09 g, 2.5 mmol) was combined withanhydrous sodium carbonate powder (1.50 g, 14.1 mmol), 10 mL anhydrousacetonitrile, and benzyl bromide (0.33 mL, 2.75 mmol). The reaction wasstirred overnight at room temperature under nitrogen, and thenconcentrated under reduced pressure. The residue was suspended in 15 mLethanol, 10 mL of 10% NaOH solution was added, and the reaction wasstirred for 1 hour. The ethanol was removed under vacuum and the residuewas partitioned between water and dichloromethane. The solution wasadjusted to pH 8.5 using 3 N HCl, separated and extracted again withdichloromethane (2×25 mL). The solution was dried (Na₂SO₄/MgSO₄) andconcentrated under reduced pressure. The residual oil was purified bychromatography on silica gel (2% NH₄OH in EtOAc/CH₂Cl₂) to give 0.81 g(1.93 mmol) of3-((S)-((2S,5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenolas a white foam.

[0383]¹H NMR (500 MHz, d₆-DMSO): δ 9.33 (s, 1H), 7.45 (dd, J=3, 4.9 Hz,1H), 7.25-7.36 (m, 4H), 7.17-7.21 (m, 2H), 7.13 (t, J=7.8 Hz, 1H), 6.99(d, J=4.9 Hz, 1H), 6.66-6.71 (m, 3H), 5.00 (s, 1H), 3.81 (d, J=13.2 Hz,1H), 3.15 (d, J=12.9 Hz, 1H), 2.65 (dd, J=2.6, 11.2 Hz, 1H), 2.58 (dd,J=2.4, 11 Hz, 1H), 2.42 (br s, 1H), 1.86-1.94 (m, 2H), 1.02 (d, J=5.7Hz, 3H), 1.01 (d, J=5.7 Hz, 3H). MS: 393 (M+1, 100%), 189 (32%).Calculated for C₂₄H₂₈N₂OS 0.3 C₄H₈O: C, 72.24; H, 7.31; N, 6.69; S,7.65%. Found: C, 72.23; H, 7.24; N, 6.74; S, 7.74%.

[0384] This material was converted to the hydrochloride salt andprecipitated from CH₂Cl₂/Et₂O as an amorphous, white solid. Calculatedfor C₂₄H₂₈N₂OS.0.3 C₄H₁₀O.1.3 HCl: C, 65.49; H, 7.04; N, 6.06; S, 6.94;Cl, 9.97%. Found: C, 65.70; H, 7.34; N, 6.09; S, 6.97; Cl, 9.95%.

EXAMPLE 25

[0385]3-((S)-((2S,5R)-4-(2,6-Difluorobenzyl)-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol

[0386] The compound of this Example was prepared by following thesynthesis procedure as described in Example 24 using 2,6-difluorobenzylbromide.

[0387] The free base was obtained as an off-white foam in 84% yield from3-((S)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol.

[0388]¹H NMR (500 MHz, d₆-DMSO): δ 9.31 (s, 1H); 7.45 (dd, J=3.0, 4.9Hz, 1H); 7.35-7.38 (m, 1H); 7.13 (s, 1H); 7.12 (t, J=7.7 Hz, 1H); 7.05(t, J=7.8 Hz, 1H); 7.02-7.07 (m, 1H); 6.96 (d, J=4.9 Hz, 1H); 6.66 (brd, J=8.0 Hz, 2H); 6.64 (br s, 1H); 5.02 (s, 1H); 3.83 (d, J=12.6 Hz,1H); 3.26 (d, J=7.4 Hz, 1H); 2.58-2.62 (m, 2H); 2.50 (m, 1H-obscured byDMSO peak); 2.45 (m, 1H); 2.32 (m, 1H); 1.97 (t, J=9.2 Hz,1H); 1.77 (m,1H); 1.05 (d, J=6.0 Hz, 3H); 1.01 (d, J=6.0 Hz, 3H).

[0389] This material was converted to the hydrochloride salt andprecipitated from CH₂Cl₂/Et₂O as an amorphous, off-white solid.Calculated for C₂₄H₂₆F₂N₂OS 0.1 C₄H₁₀O 0.6H₂O 1.05 HCl:C, 60.43;H,6.07;N, 5.78; S, 6.61; Cl, 7.68%. Found: C, 60.33; H, 6.02; N, 5.71; S,6.46; Cl, 7.55%. MS: 429 (M+1, 100%), 189 (11%).

EXAMPLE 26

[0390](+)-3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide

[0391] 3-Fluoro-N-methylaniline was prepared from 3-fluoroaniline usinga modified reductive amination. First, 1-hydroxymethylbenzotriazole wasprepared by adding 37% aqueous formaldehyde to benzotriazole at 40° C.in a 1:1 ratio and cooling to room temperature to precipitate theproduct. After filtration the hydroxymethylbenzotriazole (125 g) washeated to reflux in toluene with 3-fluoroaniline (92.2 g). Water wasremoved azeotropically using a Dean-Stark trap. After three hours, themixture was cooled to room temperature, then refrigerated for severalhours to complete precipitation. The white crystalline solid wascollected by filtration, yielding 174.2 g (86.6%) of1-((3-fluoroanilino)methyl)-1H-benzotriazole.

[0392] 1-((3-Fluoroanilino)methyl)-1H-benzotriazole (173.9 g) wasslurried in dry tetrahydrofuran. Sodium borohydride (32.5 g) was addedportionwise to the mixture at room temperature. After addition wascomplete, the mixture was heated at reflux for 4 hours. The solution wascooled and poured slowly into 400 mL of 5 M hydrochloric acid with iceand stirred for 1 hour at room temperature. The solution pH was adjustedto 9-10 using 10 M sodium hydroxide solution. The product was extractedusing diethyl ether. The ether extracts were washed successively with 1M sodium hydroxide solution, saturated sodium chloride solution, andwater. The organic phase was dried over sodium sulfate and evaporatedunder reduced pressure to yield 87.5 g (97%) of 3-fluoro-N-methylanilineas a colorless oil. [NMR (200 MHz, DMSO-d₆): δ 2.76 (s, 3H); 3.41 (br s,1H); 6.59-6.92 (m, 3H); 7.27 (q, J=8.0 Hz, 1H)].

[0393] 3-Carboxybenzaldehyde was slurried in thionyl chloride (6 mL). Areflux condenser fitted with a calcium chloride drying tube was placedon the flask. The reaction was placed in an oil bath and heated at abath temperature maintained below 100° C. The mixture was allowed toreflux until a clear solution was obtained and for 5-10 additionalminutes before cooling to room temperature. The solution was dilutedwith anhydrous toluene, and all volatiles were removed under vacuum.

[0394] The crude acid chloride was dissolved in dichloromethane andcooled in an ice/water bath. Triethylamine (6 mL) was added dropwise viaan addition funnel, followed by N-methyl-3-fluoroaniline (1.83 g) indichloromethane. The cloudy solution was allowed to warm to roomtemperature over 1 hour. Water was added and the product was extractedwith dichloromethane. The organic layer was washed with water andsaturated sodium chloride solution and dried over sodium sulfate, andthe solvent was removed under vacuum.N-(3-Fluorophenyl)-3-formyl-N-methylbenzamide (3.20 g) was obtained as alight golden oil (93% unchromatographed yield). [NMR (300 MHz, DMSO-d₆):δ 3.38 (s, 3H); 6.94-7.02 (m, 2H); 7.18-7.29 (m, 2H); 7.46 (t, J=7.7 Hz,1H) 7.55 (d, J=7.6 Hz, 1H); 7.81 (m, 2H); 9.90 (s, 1H)].

[0395] 2R,5s⁻¹-Allyl-2,5-dimethylpiperazine (as prepared in Example 1,1.28 g, 8.3 mMol.), benzotriazole (1.00 g, 8.4 mMol, 1.01 eq., Aldrich),and N-(3-fluorophenyl)-3-formyl-N-methylbenzamide (2.14 g, 8.3 mMol.)were mixed in 80 mL of dry toluene with one drop of triethylamine. Themixture was placed in an oil bath maintained below 140° C. (bathtemperature. The flask was attached to a Dean-Stark trap and refluxcondenser to allow the azeotropic removal of water. The mixture wasrefluxed for 2-3 hours, under a nitrogen atmosphere, then the majorityof the toluene was removed under reduced pressure. The crude adduct wasused in the following procedure without isolation.

[0396] The crude benzotriazole adduct was dissolved in ˜10 mL oftetrahydrofuran and added to a solution of3-phenoxy-tert-butyldimethylsilane magnesium bromide (as prepared inExample 17, 1.75 equiv.) via a double-ended needle. After stirring undernitrogen at room temperature for 2 hours, the reaction was quenched with3-4 mL of saturated ammonium chloride solution. Having stirred this forabout half an hour, a generous amount of anhydrous magnesium sulfate wasadded. Filtering and concentrating the solution under reduced pressuregave the crude silyl ether contaminated with benzotriazole by-product.This residue was dissolved in ethyl acetate and extracted with 10%aqueous NaOH solution three times to remove most of the benzotriazole.The organic layer was washed with saturated sodium chloride solution,dried over sodium sulfate/magnesium sulfate, and the ethyl acetate wasremoved under reduced pressure.

[0397] The t-butyldimethylsilyl protecting group was removed bydissolving the residue in 40 mL of tetrahydrofuran and adding 40 mL of3N aqueous HCl at room temperature. The solution warmed upon acidaddition. The mixture was stirred for 90 minutes at room temperature.The reaction was concentrated under reduced pressure to remove most ofthe organic solvent. The residue was partitioned between water and asolution of diethyl ether:ethyl acetate/3:2. The acidic aqueous layerwas extracted twice with a solution of diethyl ether ethyl acetate/3:2.

[0398] The aqueous layer was adjusted to pH=2 using aqueous NaOHsolution, at which point cloudiness persisted and a dark oil began toprecipitate. Methylene chloride (˜100 mL) was added and stirred briskly.This was separated and the aqueous layer was again washed with moremethylene chloride. The combined organic extract was partitioned withwater, and while stirring vigorously was adjusted to pH=9 using aqueousNaOH solution. This was then separated and the aqueous layer was againwashed with more methylene chloride.

[0399] The combined extract was dried over sodium sulfate/magnesiumsulfate, and the solvent was evaporated under reduced pressure. Thecrude material was chromatographed on silica gel column (roughly 20-25 gof silica gel per gram of crude material) eluting first with methylenechloride, then with 20% ethyl acetate in methylene chloride to removethe less polar contaminant. Then, the column was eluted with a solutionof ethyl acetate containing 2% ammonium hydroxide (solution A) in agradient with methylene chloride (solution B), quickly increasing inpolarity from 25% to 100% (solution A in B).

[0400] The desired fractions were combined and the solvent was removedunder reduced pressure. A 10:1 mixture of diastereomers (approx. 2.6 g)was obtained. Pure product was obtained by crystallization from a hotsolution of ethyl acetate (5-10 mL) followed by slow addition of heptane(10-20 mL) and gradual cooling to give 1.78 g of(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamideas an off-white crystalline solid (m.p.=144-145° C.) with >98% isomericpurity (as determined by NMR). NMR (200 MHz, DMSO-d₆): δ 0.84 (d, J=6.0Hz, 3H); 0.97 (d, J=5.9 Hz, 3H); 1.69 (dd, J₁=7.7 Hz, J₂=10.7 Hz, 1H);2.01 (dd, J₁=7.4 Hz, J₂=10.7 Hz, 1H); 2.28 (br. d, J=8.3 Hz, 1H);2.40-2.52 (m, 2H); 2.67 (br d, J=10.5 Hz, 1H); 2.82 (dd, J₁=7.6 Hz,J₂=13.2 Hz, 1H); 3.17 (br. d, J=14.0 Hz, 1H); 3.34 (s, 3H); 4.80 (s,1H); 5.10 (d, J=10.1 Hz, 1H); 5.17 (d, J=17.3 Hz, 1H); 5.70-5.84 (m,1H); 6.42 (d, J=7.1 Hz, 1H); 6.56 (s, 1H); 6.65 (d, J=8.3 Hz, 1H);6.90-7.32 (m, 9H); 9.31 (s, 1H). Mass spectrum (C₁-CH₄)

[0401] m/z: 488 (m+1, 100%), 334 (39%), 153 (87%). [α]_(D) ²⁰=+4.9°(abs. ethanol, c=1.2).

EXAMPLE 27

[0402]3-((R)-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide

[0403]3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (Example 26, 4.88 g, 10 mmol),N-phenyltrifluoromethane-sulfonimide (3.82 g, 10.7 mmol), andtriethylamine (3.1 mL, 22 mmol) were dissolved in 75 mL dichloromethaneand stirred overnight at room temperature under nitrogen. Afterconcentrating under reduced pressure, the residue was dissolved in 100mL ethyl acetate and washed with Na₂CO₃ solution (3×100 mL), water(1×100 mL), and brine (1×100 mL). The solution was dried (Na₂SO₄/MgSO₄)and concentrated under reduced pressure. The residual oil was purifiedby chromatography on silica gel (2% NH₄OH in EtOAc/CH₂Cl₂) to give 6.1 g(9.8 mmol) of a viscous, golden yellow oil.

[0404] The allyl portion was removed using Pd(dba)₂/DPPB in the presenceof thiosalicylic acid by the method of Genet [J.P. Genet, S.Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270(1995)]. The reaction was concentrated and the residue was dissolved in50 mL ethyl acetate and 100 mL diethyl ether. After washing this withNa₂CO₃ solution (3×100 mL) and water (1×100 mL), the organic solutionwas extracted with 3 N HCl (3×20 mL) and 1 N HCl (1×20 mL). The acidicextract was adjusted to pH 8.5 using NaOH solution and extracted withdichloromethane (3×25 mL). The solution was dried (Na₂SO₄/MgSO₄) andconcentrated under reduced pressure. The residual oil was purified bychromatography on silica gel (2% NH₄OH in EtOAc/CH₂Cl₂) to give 4.44 g(7.6 mmol) of a viscous, deep amber-orange colored oil.

[0405] The above free amine (0.867 g, 1.5 mmol) was combined withanhydrous sodium carbonate powder (0.81 g, 7.64 mmol), 10 mL anhydrousacetonitrile, and benzyl bromide (0.20 mL, 1.68 mmol). The reaction wasstirred overnight at room temperature under nitrogen, and thenconcentrated under reduced pressure. The residue was suspended in 15 mLethanol, 10 mL of 10% NaOH solution was added, and the reaction wasstirred for 30 minutes. The ethanol was removed under vacuum and theresidue was partitioned between water and dichloromethane. The solutionwas adjusted to pH 8.5 using 3 N HCl, separated and extracted again withdichloromethane (2×25 mL). The solution was dried (Na₂SO₄/MgSO₄) andconcentrated under reduced pressure. The residual oil was purified bychromatography on silica gel (2% NH₄OH in EtOAc/CH₂Cl₂) to give 0.44 g(0.82 mmol) of the desired product as a white foam.

[0406]¹H NMR (500 MHz, d₆-DMSO): δ 9.32 (s, 1H), 7.19-7.30 (m, 10H),7.05-7.09 (m, 2H), 6.98 (dt, J=2.3, 8.4 Hz, 1H), 6.89 (dd, J=1.0, 8.0Hz, 1H), 6.63 (dd, J=1.0, 8.0 Hz, 1H), 6.57 (br s, 1H), 6.43 (d, J=7.4Hz, 1H), 4.77 (br s, 1H), 3.77 (d, J=13.7 Hz, 1H), 3.36 (s, 3H), 3.21(d, J=13.7 Hz,1H), 2.59 (d, J=9.0 Hz,1H), 2.50 (m, 2H obscured by DMSOpeak), 2.35 (d, J=9.0 Hz,1H), 1.92 (dd, J=7.4, 10.9 Hz, 1H), 1.74 (dd,J=7.4, 10.9 Hz,1H), 0.99 (d, J=6.1 Hz, 3H), 0.92 (d, J=6.1 Hz, 3H). MS:538 (M+1, 100%), 334 (20%). Calculated for C₃₄H₃₆FN₃O₂ 0.15 C₄H₈O₂ 0.06CH₂Cl₂: C, 74.88; H, 6.77; N, 7.56; F, 3.42%. Found: C, 74.72; H, 6.96;N, 7.38; F, 3.79%.

[0407] This material was converted to the hydrochloride salt andprecipitated from CH₂Cl₂/Et₂O as an amorphous, off-white solid.Calculated for C₃₄H₃₆FN₃O₂ 0.1 C₄H₁₀O.1.1 HCl.0.1H₂O: C,70.39; H, 6.58;N, 7.16; Cl, 6.64%. Found: C, 70.41; H, 6.56; N, 7.13; Cl, 6.60%.

EXAMPLE 28

[0408]3-((R)-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluoro-phenyl)-N-methylbenzamide

[0409] The compound of this Example was prepared by following thesynthesis procedure as described in Example 27 using 4-fluorobenzylbromide.

[0410] The free base was obtained as an off-white foam in 58% yield from3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide.

[0411]¹H NMR (600 MHz, d₆-DMSO): δ 9.29 (s,1H), 7.16-7.29 (m, 7H),7.02-7.10 (m, 4H), 6.97 (dt, J=2.3, 8.4 Hz, 1H), 6.88 (dd, J=1.2, 8.0Hz, 1H), 6.61 (dd, J=1.2, 8.0 Hz, 1H), 6.55 (br s, 1H), 6.42 (br d,J=7.3 Hz, 1H), 4.74 (br s, 1H), 3.71 (br d, J=13.0 Hz, 1H), 3.34 (s,3H), 3.19 (br d, J=13.0 Hz, 1H), 2.56 (d, J=9.0 Hz, 1H), 2.48 (m, 2Hobscured by DMSO peak), 2.32 (d, J=9.0 Hz, 1H), 1.90 (dd, J=7.2, 11.1Hz, 1H), 1.72 (dd, J=7.2, 11.1 Hz, 1H), 0.97 (d, J=6.1 Hz, 3H), 0.90 (d,J=6.1 Hz, 3H).MS: 556 (M+1, 100%), 334 (26%).

[0412] This material was converted to the hydrochloride salt andprecipitated from CH₂Cl₂/Et₂O as an amorphous, off-white solid.Calculated for C₃₄H₃₅F₂N₃O₂.0.5H₂O.0.95 HCl: C, 68.14; H, 6.21; N, 7.01;Cl, 5.62%. Found: C, 68.17; H, 6.27; N, 6.91; Cl, 5.63%.

EXAMPLE 29

[0413]4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide

[0414] Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH, 10mmol)) was washed with pentane (2×7 mL), and tetrahydrofuran (10 mL) wasadded. The product from Example 11,4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(1.007 g, 2.0 mmol) was dissolved in the stirred suspension, and wheneffervescence had subsided, methyl iodide (249 μL, 568 mg, 4 mmol) wasadded. The reaction mixture was sealed under nitrogen and stirred for 6h at ambient temperature. The reaction mixture was evaporated todryness, and the residue was partitioned between ethyl acetate (15 mL)and water (5 mL). The organic layer was separated, the aqueous portionextracted with ethyl acetate (2×10 mL) and the combined organic extractswere dried over anhydrous sodium sulfate. The organic solution wasevaporated to a pale yellow gum, which on trituration and sonicationwith pentane yielded4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamideas a flocculent white solid (0.798 g, 77% after drying at roomtemperature and 5 mm Hg). Calc. for C₃₂H₄₀FN₃O₂ 0.25H₂O: C, 73.60; H,7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84% ¹HNMR (CDCl₃, 300 MHz); δ 1.09 (d, J=6.2 Hz, 6H, superimposed on br m,3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br m, 2H); 2.66 (m, 3H); 3.15(d, J=13.3 Hz, 1H); 3.27 (br m, 2H); 3.54 (br m, 2H); 3.78 (s, 3H); 3.84(d, J=13 Hz, 1H); 5.10 (s, 1H); 6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H);6.96 (t, J=8.2 Hz, 2H); 7.26 (m, 5H); 7.46 (d, J=7.8 Hz, 2H).

EXAMPLE 30

[0415]N,N-Diethyl-3-[(R)-[(2S,SR)-4-(3-hydroxybenzyl)-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]benzamide

[0416] The title compound was made in identical fashion to the compoundof Example 17, with the exception that 3-methoxyphenyl magnesium bromidewas substituted for 3-(tert-butyldimethylsilyloxy)phenyl magnesiumbromide.

[0417] Calc. for C₃₂H₄₁N₃O₃.HCl: C, 66.98; H, 7.75; N, 7.32; Cl, 6.80.

[0418] Found: C, 66.92; H, 7.64; N, 7.21; Cl, 6.61.

EXAMPLE 31

[0419]N,N-Diethyl-3-{(R)-(3-hydroxyphenyl)-[(2S,5R)-4-(3-methoxybenzyl)-2,5-dimethylpiperazin-1-yl]methyl}benzamide

[0420] The title compound was made in identical fashion to the compoundof Example 17, with the exception that 3-methoxybenzaldehyde wassubstituted for 3-hydroxybenzaldehyde. Calc. for C₃₂H₄₁N₃O₃.HCl.H₂O: C,67.41; H, 7.78; N, 7.37; Cl, 6.22. Found: C, 66.80; H, 7.73; N, 7.21;Cl, 6.63.

EXAMPLE 32

[0421](3-{(2R,5S)-4-[(R)-(3-Diethylcarbamoylphenyl)-(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}phenoxy)aceticacid 3-Hydroxybenzaldehyde (2.00 g, 16.4 mmol) was dissolved in 25 mL ofdry tetrahydrofuran under nitrogen with 3.5 g of potassium carbonate and3.01 g (18.0 mmol) of ethyl bromoacetate. The reaction was heated atreflux for 6 hr, then cooled to room temperature and filtered frominorganic salts. The filtrate was evaporated, redissolved in 30 mL ofmethylene chloride, washed with 2×15 mL of water, and dried over sodiumsulfate. Evaporation of solvent gave 2.92 of ethyl3-formylphenoxyacetate as a yellow oil.

[0422]3-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxybenzyl)-N,N-diethylbenzamide(0.79 g, 1.5 mmol, as made in Example 17) and ethyl3-formylphenoxyacetate (0.62 g, 3.0 mmol) were placed in a 50 mL flaskand sealed under nitrogen with 15 mL of tetrahydrofuran and 100 mg ofacetic acid. The solution was stirred at room temperature for 20minutes, and then sodium triacetoxyborohydride (0.96 g, 4.00 mmol) wasadded and the reaction was stirred overnight. The reaction mixture wasdiluted with 100 mL of ethyl acetate, washed with aqueous sodiumcarbonate and brine, and dried over anhydrous sodium sulfate.Evaporation of solvent gave 1.2 g of yellow oil. The crude diester waspurified by chromatography on silica gel with 20% ethyl acetate inmethylene chloride to give 0.56 g of ethyl(3-{(2R,5S)-4-[(R)-(3-diethylcarbamoylphenyl)-(3-trifluoromethylsulfonyloxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}phenoxy)acetate.The product was dissolved in 8 mL of 95% ethanol with 80 mg of sodiumhydroxide and stirred overnight. The ethanol was evaporated and theaqueous solution was extracted with 2×2 mL of 1:1 diethyl ether/ethylacetate. Dilute hydrochloric acid was added dropwise to the aqueouslayer to give maximum precipitate, which was collected by filtration.The collected yellow solid was triturated with a mixture of diethylether (4 mL), methanol (4 mL), hexane (2 mL), and ethyl acetate (1.5 mL)and filtered. The remaining solid was collected by filtration anddissolved in 5 mL of methylene chloride. Diethyl ether was added withstirring to precipitate the product, which was collected by filtrationand dried to give 277 mg of(3-{(2R,5S)-4-[(R)-(3-diethylcarbamoylphenyl)-(3-hydroxyphenyl)-methyl]-2,5-dimethylpiperazin-1-ylmethyl}phenoxy)acetic acid as a white solid. Calc. for C₃₃H₄₁N₃O₅.1.4 CH₂Cl₂:C, 60.89; H, 6.51; N, 6.19. Found: C, 60.98; H, 6.56; N, 6.23.

EXAMPLE 33

[0423](3-{(2R,5S)-4-[(R)-(3-Diethylcarbamoylphenyl)-(3-methoxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}phenoxy)aceticacid

[0424] The title compound was made from the compound of Example 30 byalkylating with methyl chloroacetate according to the procedure ofExample 14.

[0425] Calc. for C₃₄H₄₃N₃O₅.0.65 CH₂Cl₂: C, 66.17; H, 7.10; N, 6.68.

[0426] Found: C, 66.15; H, 7.49; N, 6.51.

EXAMPLE 34

[0427]N,N-Diethyl-3-[(R)-[(2S,5R)-4-(3-methoxybenzyl)-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]benzamide

[0428] The title compound was made in identical fashion to the compoundof Example 17 by substituting 3-methoxyphenyl magnesium bromide for3-(tert-butyldimethylsilyloxy)phenyl magnesium bromide and bysubstituting 3-methoxybenzaldehyde for 3-hydroxybenzaldehyde.

[0429] Calc. for C₃₃H₄₃N₃O₃.1.6 HCl: C, 67.40; H, 7.64; N, 7.15; Cl,9.65.

[0430] Found: C, 67.39; H, 7.66; N, 7.00; Cl, 9.61.

EXAMPLE 35

[0431]4-(alpha-R)-alpha-((2S,5R)-4-(Cyclopropylmethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

[0432] The title compound was made from4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide(Example 10) by an essentially identical procedure as Example 11, usingcyclopropylmethyl bromide as the alkylating agent.

[0433] Calc. for C₃₃H₄₃N₃O₃.0.75H₂O: C, 72.61; H, 8.81; N, 9.07.

[0434] Found: C, 72.50; H, 8.56; N, 8.68.

EXAMPLE 36

[0435]4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide

[0436] A solution of4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethyl-sulfonyloxybenzyl)-N,N-diethylbenzamide(3.522 g, 6.0 mmol, Example 10) and sodium iodide (90 mg, 0.6 mmol) inacetonitrile (30 mL) was stirred during the addition of triethylamine(3.0 mL, 2.186 g, 21.6 mmol) followed by 3-fluorobenzyl bromide (1.472mL, 2.268 g, 12.0 mmol). An immediate turbidity was observed, thickeningto a white crystalline precipitate as the reaction progressed. Thereaction mixture was sealed under nitrogen and stirred at roomtemperature. After 18 h the solvent was removed by evaporation underreduced pressure and the residue partitioned between ethyl acetate (30mL) and saturated sodium bicarbonate solution (10 mL). The organic layerwas separated and the aqueous portion further extracted with ethylacetate (3×15 mL). The combined extract and washings were dried oversodium sulfate, the solution evaporated to dryness and re-dissolved inethyl acetate (˜5 mL). The solution was applied to an intermediate (4×15cm) Biotage column and eluted with ethyl acetate, collecting fractionsof 20 mL. Fractions containing pure material as evidenced by thin layerchromatography (silica, EM60F₂₅₄, developed with ethyl acetate, R_(f)0.9) were pooled and evaporated to yield a yellow/orange oil (3.01 g).The oil was dissolved in ethanol (30 mL) and aqueous sodium hydroxidesolution (10.0 mL, 2.5-M, 25 mmol) was added. The initially cloudysuspension clarified to a yellow solution that was set aside at roomtemperature for 3 h. The mixture was evaporated under reduced pressureto remove ethanol, and evaporation continued until condensation of waterindicated complete removal of ethanol. The cloudy suspension of the oilysodium salt of the phenol was diluted to 20 mL with water to yield aclear yellow solution. The pH of the strongly basic solution wasadjusted to 8.5-9 by passage of carbon dioxide gas (from dry ice) toyield a dense white flocculent precipitate. The solid was removed byfiltration and washed thoroughly with cold water, including twicere-slurrying of the precipitate on the sinter with fresh water. Thesolid was air-dried on the sinter overnight, then dried under vacuum at1 mm Hg at room temperature to yield4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamideas a white solid (2.062 g, 67%) Calc. for C₃₁H₃₈FN₃O₂.0.5H₂O: C, 72.63;H, 7.67; N, 8.20; F, 3.71. Found C, 72.77; H, 7.52; N, 8.18; F, 3.61%.¹H NMR (CDCl₃, 300 MHz); δ 1.05 (d, J=5.9 Hz, 6H); 1.11 (br m, 3H); 1.23(br m, 3H); 2.00 (m, 2H); 2.59 (br m, 2H); 2.62 (d, J=11.4 Hz, 1H); 2.68(d, J=11.0 Hz, 1H); 3.19 (d, J=13.6 Hz, 1H); 3.28 (br m, 2H); 3.54 (brm, 2H); 3.89 (d, J=13.9 Hz, 1H); 5.01 (s, 1H); 6.15 (v br s, 1H); 6.63(s, 1H); 6.70 (m, 2H); 6.91 (t, J=8.8 Hz, 1H); 7.07 (m, 2H); 7.14 (t,J=7.8 Hz, 1H); 7.22 (m, 1H); 7.28 (d, J=8.2 Hz, 2H); 7.44 (d, J=8.1 Hz,2H).

EXAMPLE 37

[0437]4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl)-benzyl)-N,N-diethylbenzamide

[0438] 4-Hydroxybenzaldehyde (488 mg, 4.0 mmol) was dissolved in asolution of4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide(759 mg, 2.0 mmol, Example 2) and acetic acid in tetrahydrofuran (10mL). Sodium triacetoxy borohydride (848 mg, ˜4 mmol) was addedportionwise over 5 min, then the reaction mixture sealed under nitrogenand stirred overnight at room temperature. The reaction mixture wasevaporated to dryness and the residue partitioned between water (6 mL)and ethyl acetate (20 mL). The aqueous solution was further extractedwith ethyl acetate (2×10 mL) and the combined extract and washingsdiluted with an equal volume of ether. The organic solution wasextracted with 3M-HCl and the acidic aqueous solution carefullyneutralized, initially with 5M-NaOH, then saturated NaHCO₃. At pH 4 thesolution was filtered through a 0.45 mM syringe filter to remove a smallquantity of an off-white gummy solid. The pH of the filtrate wasadjusted to 8.5 to precipitate a flocculent white solid which wasfiltered off, washed well with cold water and dried overnight at 2 mm Hgat room temperature to yield4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl)-benzyl)-N,N-diethylbenzamide(73.05%). Calc. for C₃₁H₃₉N₃O₂ 1.5H₂° C., 72.62; H, 8.26; N, 8.20. FoundC, 72.58; H, 7.83; N, 8.40% ¹H NMR (1% NaOD in D2O, 300 MHz); δ 0.75 (brm, 3H); 0.81 (br d, J=7.3 Hz, 6H); 0.94 (br m, 3H); 1.71 (m, 1H); 1.84(m, 1H); 2.29 (m, 2H); 2.49 (br m, 2H); 2.91 (m, 3H); 3.22 (m, 2H); 3.57(br m, 2H); 5.02 (s, 1H); 6.39 (d, J=7.5 Hz, 2H); 6.80 (d, J=7.3 Hz,2H); 7.01 (m, 7H); 7.17 (m, 2H).

EXAMPLE 38

[0439]4-(alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide

[0440] Alkylation of4-((alpha-R)-alpha-((2S,5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide(Example 12) with methyl iodide according to the procedure of Example 29gave the title compound. Calc. for C₃₂H₄₁N₃O₂: C, 76.92; H, 8.27; N,8.41.

[0441] Found: C, 76.84; H, 8.34; N, 8.29.

EXAMPLE 39

[0442]4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide

[0443]4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxy-benzyl)-N,N-diethylbenzamide(from Example 10, 527.6 mg, 1.0 mmol) was dissolved in acetonitrile (4.0mL) and sodium iodide (15 mg, 0.1 mmol) added. The suspension wasstirred during the addition of triethylamine (500 μL (363 mg), 3.59mmol), followed by 2-fluorobenzyl bromide (241 μL (378 mg), 2.0 mmol).The reaction mixture was sealed under nitrogen and stirred overnight atroom temperature. The reaction mixture was evaporated to dryness andpartitioned between ethyl acetate (10 mL) and saturated aqueous sodiumbicarbonate solution (2.5 mL). The supernatant organic layer wasremoved, and the aqueous portion washed with ethyl acetate (3×10 mL).The combined organic extract and washings were dried over anhydroussodium sulfate and evaporated to a golden oil. The residue was dissolvedin ethyl acetate (7 mL), applied to a pre-packed (Biotage) column andeluted with ethyl acetate. Pure fractions containing desired product, asevidenced by t.l.c. (silica gel, EM60F₂₆₄, 100% ethyl acetate,R_(f)=0.77) were evaporated to dryness to yield the intermediate4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide(610 mg), as a yellow oil which was used without further purification.The oil was dissolved in ethanol (7 mL) and aqueous 2.5 M (10%) sodiumhydroxide solution (5 mL, 12.5 mmol) was added. The reaction mixture wasset aside at room temperature for 5 h, then the ethanol removed byevaporation. The oily suspension of the sodium salt was clarified by theaddition of water (5 mL), and the pH of the solution adjusted to 9-10 bythe passage of gaseous carbon dioxide (from dry ice). The copious whiteprecipitate was washed well with water and dried under vacuum (2 mm Hg)at room temperature overnight to yield4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamideas a white solid (431 mg, 85.6%). Calc. for C₃₁H₃₈FN₃O₂: C,73.93; H,7.61; N, 8.34; F, 3.77. Found C, 73.96; H, 7.67; N, 8.29; F, 3.75%. ¹HNMR (CDCl₃, 300 MHz); δ 1.05 (d, J=6.1 Hz, 3H); 1.09 (d, J=6 Hz, 3H);1.12 (br m, 3H); 1.24 (br m, 3H); 1.96 (t, J=10 Hz, 1H); 2.07 (t, J=10Hz, 1H); 2.56 (br m, 2H); 2.60 (d, J=11 Hz, 1H); 2.72 (d, J=11 Hz, 1H);3.29 (br m, 2H); 3.36 (d, J=14 Hz, 1H); 3.55 (br m, 2H); 3.89 (d, J=14Hz, 1H); 5.13 (s, 1H); 6.57 (s, 1H); 6.66 (d, J=10 Hz, 2H); 7.00 (t, J=9Hz, 1H); 7.07 (t, J=7.5 Hz, 1H); 7.10 (t, J=8 Hz, 1H); 7.20 (m, 1H);7.27 (d, J=8 Hz, 2H); 7.38 (t, J=7 Hz, 1H); 7.43 (d, J=7 Hz, 2H).

[0444]4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamidewas alkylated with methyl iodide by a procedure essentially identical tothat of Example 29 to give4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide.

[0445] Calc. for C₃₂H₄₀FN₃O₂.0.1H₂O: C, 73.99; H, 7.80; N, 8.09; F,3.66.

[0446] Found: C, 73.98; H, 7.86; N, 8.00; F, 3.77.

EXAMPLE 40

[0447]4-[(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide

[0448] 3-(t-Butyl-dimethylsilanyloxy)benzaldehyde.t-Butyldimethylchlorosilane (26.01 g; 172.56 mmol) was added to asolution of 3-hydroxybenzaldehyde (20.7 g; 164.35 mmol) and imidazole(27.97 g; 410.9 mmol) in chloroform (300 mL) under nitrogen at 0° C. Thereaction was allowed to warm to room temperature and stirred overnight.The reaction mixture was washed with water (100 mL×3) and brine (100mL), dried over anhydrous sodium sulfate and concentrated to give crudeproduct (29.56 g), which was purified by column chromatography on silicagel eluting with (i) pentane and (ii) 3% ethyl acetate in pentane togive 3-(t-butyl-dimethylsilanyloxy)benzaldehyde (21.0 g; 54%). ¹H NMR(300 MHz, CDCl₃) δ 9.93 (s, 1H), 7.45 (d, 1H, J=7.5 Hz), 7.38 (dd, 1H,J=7.5, 7.5 Hz), 7.31 (d, 1H, J=1.0 Hz), 7.09 (1H, dd, J=7.5, 1.0 Hz),0.98 (s, 9H), 0.20 (s, 6H).

[0449] 4-Iodo-N,N-dimethyl-benzenesulfonamide. Dimethylamine (100 mL of2.0 M solution in tetrahydrofuran; 200 mmol) was added to a solution of4-iodobenzenesulfonyl chloride (54.76 g; 181 mmol) in pyridine (300 mL)at 0° C. under N₂, followed by the addition of4-N,N-dimethylaminopyridine (15 mg). The reaction was allowed to warm toroom temperature and was stirred under N₂ for 48 hrs. The reactionsolution was poured into 1.2 liter of water, and the precipitatedproduct was collected by filtration and rinsed with water (300 mL×2).The solid was dissolved in ethyl acetate (500 mL) and washed with 5%aqueous hydrochloric acid (300 mL×3), water (300 mL×2) and brine (300mL). The organic solution was dried over anhydrous sodium sulfate andconcentrated to give 4-iodo-N,N-dimethyl-benzenesulfonamide (49.46 g;88%) as a white solid, which was used in the next reaction withoutfurther purification. ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, 2H, J=8.5 Hz),7.46 (d, 2H, J=8.5 Hz), 2.69 (s, 3H).

[0450]4-{(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)[3-(tert-butyl-dimethylsilanyloxy)-phenyl]methyl}-N,N-dimethylbenzenesulfonamide.

[0451] Part 1: Preparation of iminium intermediate: To a 3-neck flaskequipped with a Soxhlet extractor filled with 3A molecular sieves wasadded benzotriazole (618 mg; 5.19 mmol),3-(t-butyl-dimethylsilanyloxy)benzaldehyde (1.227 g; 5.19 mmol),(+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine (961 mg; 6.23 mmol, preparedby the method described in Example 1 for(−)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, but usingdi-p-toluoyl-L-tartaric acid as the resolving agent) and toluene (150mL). The solution was refluxed under N₂ for 20 h. The solution wascooled to room room temperature under N₂.

[0452] Part 2: Preparation of Grignard reagent: Isopropylmagnesiumchloride (6.91 mL of 2.0 M solution in tetrahydrofuran; 13.82 mmol) wasadded to a solution of 4-iodo-N,N-dimethylbenzenesulfonamide (4.3 g;13.82 mmol) at room temperature under N₂ and stirred for 20 minutes.

[0453] Part 3: The solution of Part I was added to the Grignard reagentprepared in Part 2 dropwise via a syringe at room temperature under N₂in a span of 35 minutes while the reaction solution was stirredvigorously. The reaction was stirred at room temperature overnight andquenched by the addition of saturated aqueous ammonium chloride (10 mL).The resulting mixture was diluted by the addition of ethyl acetate (120mL) and water (120 mL). The cloudy mixture was filtered thru a Celite®pad. The filtrate was poured into a separate funnel. The organic layerand water layer were separated. The organic layer was extracted with 10%aqueous sodium hydroxide (75 mL×4), washed with water (100 mL×3) andbrine (100 mL), dried (sodium sulfate) and concentrated to give crudeproduct, which was purified by silica gel chromatography conducted onCombiFlash™ Sq 16×(gradient: 100% CH₂Cl₂ to 7% MeOH in CH₂Cl₂) to give4-{(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl)[3-(tert-butyl-dimethylsilanyloxy)-phenyl]methyl}-N,N-dimethylbenzenesulfonamide(1.3 g; 45%). ¹H NMR (300 MHz, CDCl₃) δ 7.71 (d, 2H, J=8.0 Hz), 7.35 (d,2H, J=8.0 Hz), 7.12 (dd, 1H, J=8.0, 8.0 Hz), 6.92 (s, 1H), 6.84 (d, 1H,J=8.0 Hz), 6.71 (d, 1H, J=8.0 Hz), 5.82 (1H, m), 5.23-5.11 (m, 3H), 3.35(dd, 1H, J=14.0, 5.5 Hz), 2.88 (dd, 1H, J=14.0, 8.0 Hz), 2.82 (dd, 1H,J=11.0, 3.0 Hz), 2.73 (s, 6H), 2.68 (dd, 1H, J=11.0, 2.5 Hz), 2.55 (m,2H), 2.16 (dd, 1H, J=11.0, 8.5 Hz), 1.85 (dd, 1H, J=11.0, 9.0 Hz), 1.18(d, 3H, J=6.0 Hz), 1.01 (d, 3H, J=6.0 Hz), 0.96 (s, 9H), 0.17 (s, 3H),0.16 (s, 3H).

[0454]4-[(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide.3 N HCl (7 mL) was added to the solution of4-{(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl)[3-(tert-butyl-dimethylsilanyloxy)-phenyl]methyl}-N,N-dimethylbenzenesulfonamide(1.3 g) in tetrahydrofuran (15 mL). The mixture was stirred at roomtemperature overnight. Water (15 mL) was added to the reaction. Thereaction mixture was extracted with diethyl ether (25 mL×3). Theremaining water layer was neutralized by 10% aqueous NaOH to pH=8-9 andthen extracted with ethyl acetate (30 mL×3). The combined ethyl acetatelayers were washed with water (20 mL×3) and brine (20 mL), dried oversodium sulfate and concentrated to give 0.83 g of crude product. Thecrude product was purified by silica gel chromatography conducted onCombiFlash™ Sq 16× (gradient: 100% CH₂Cl₂ to 7% MeOH in CH₂Cl₂) to give4-[(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide(720 mg; 70%). ¹H NMR (300 MHz, CDCl₃) δ 7.71 (d, 2H, J=8.5 Hz), 7.35(d, 2H, J=8.5 Hz), 7.14 (dd, 1H, J=8.0, 8.0 Hz), 6.89 (bs, 1H), 6.85 (d,1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0, 2.5 Hz), 5.83 (1H, m), 5.24-5.12 (m,3H), 3.32 (dd, 1H, J=13.5, 5.0 Hz), 2.86 (dd, 1H, J=13.5, 8.0 Hz), 2.78(dd, 1H, J=11.5, 3.0 Hz), 2.72 (s, 6H), 2.65 (dd, 1H, J=11.0, 2.5 Hz),2.51 (m, 2H), 2.14 (dd, 1H, J=11.5, 9.0 Hz), 1.81 (dd, 1H, J=11.0, 9.5Hz), 1.16 (d, 3H, J=6.0 Hz), 0.98 (d, 3H, J=6.0 Hz); MS (FAB, glycerol)m/z: 444 (M⁺+H), 290, 153; Found: C, 58.32; H, 6.66; N, 8.18. Calc.(C₂₄H₃₃N₃O₃S 0.8 CH₂Cl₂): C, 58.23; H, 6.82; N, 8.21.

EXAMPLE 41

[0455]4-((alpha-S)-alpha-((2R,5S)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide

[0456] 4-Carboxybenzaldehyde (100 g, 666 mmol) was added to a 2000 mL,3-necked, round bottom flask and stirred under nitrogen in 1200 mL oftoluene. Thionyl chloride (53.5 mL, 733 mmol) was added to the mixture,followed by the addition of 0.15 mL of dimethylformamide. A refluxcondenser fitted with a calcium chloride drying tube was placed on theflask. The reaction was placed in an oil bath and heated at a bathtemperature maintained at 120° C. The mixture was allowed to reflux for1 hour after a clear solution was obtained and then cooled to roomtemperature. The solution was diluted with anhydrous toluene, and allvolatiles were removed under vacuum. The crude acid chloride wasdissolved in 1500 mL of dry tetrahydrofuran and cooled in an ice/waterbath. Diethylamine (173 mL, 1.67 mol, 2.5 equivalents) was addeddropwise via an addition funnel. The cloudy solution was allowed to warmto room temperature over 1 hour and stirred overnight. The reactionmixture was filtered to remove the white crystalline diethylaminehydrochloride by-product. The crystals were washed with ethyl acetate(2×600 mL). The tetrahydrofuran filtrate was evaporated, and the residuewas dissolved in the ethyl acetate washings. The solution was washedsequentially with 1 M hydrochloric acid (2×600 mL), water (2×300 mL),dilute sodium carbonate solution (saturated: H₂O, 1:1, 2×600 mL), water(2×300 mL) and saturated sodium chloride solution (300 mL). The organiclayer was separated, dried over sodium sulfate, and the solvent wasremoved under vacuum. 4-formyl-N,N-diethylbenzamide (117.14 g) wasobtained as a light yellow oil which was used without furtherpurification (85% crude yield). ¹H NMR (300 MHz, CDCl₃): δ 1.09-1.25 (m,6H); 3.19-3.31 (d, J=6.4 Hz, 2H); 3.54-3.56 (d, J=6.6 Hz, 2H); 7.49-7.52(d, J=8.1 Hz, 2H); 7.89-7.92 (d, J=8.2 Hz, 2H); 9.98 (s, 1H).Phenylmagnesium bromide (1.0 M solution in tetrahydrofuran, 235 mL, 235mmol) was slowly added to a flask containing a cold (-78° C.) solutionof 4-formyl-N,N-diethylbenzamide (48.18 g, 235 mmol) in 500 mL of drytetrahydrofuran under nitrogen. The transfer rate was monitored tomaintain reaction temperature below −70° C. The reaction was stirred foranother 45 minutes at −78° C. and then quenched with 45 mL of saturatedaqueous ammonium chloride. After warming to room temperature, themixture was diluted with 900 mL of diethyl ether and washed with 900 mLof water followed by 230 mL of saturated sodium chloride. The etherealsolution was dried over sodium sulfate and the solvent removed to givecrude 4-(N,N-diethylcarbamoyl)benzhydryl alcohol as a light yellow oil.Crude yield was ˜92%.

[0457] The 4-(N,N-diethylcarbamoyl)benzhydryl alcohol (61.35 g, 216.5mmol) was dissolved in 1500 mL of dichloromethane and 23.69 mL (324.8mmol) of thionyl chloride was added dropwise. The reaction solution wasstirred overnight at room temperature and the solvent was removed undervacuum. The crude product was redissolved in 800 mL of toluene and thesolvent again was removed under vacuum to eliminate excess thionylchloride, providing crude 4-(N,N-diethylcarbamoyl)benzhydryl chloride asa dark oil. Crude yield=100%.

[0458] The crude 4-(N,N-diethylcarbamoyl)benzhydryl chloride (125 mmol)was dissolved in acetonitrile (300 mL). Sodium iodide (18.64 g, 125mmol), diisopropylethylamine (32.65 mL, 187 mmol), and (+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine (19.23 g, 125 mmol, prepared by themethod described in Example 1 for(−)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, but usingdi-p-toluoyl-L-tartaric acid as the resolving agent) were added. Themixture was stirred at reflux, under nitrogen, for 3 hours. Theacetonitrile was removed under reduced pressure, the reaction mixturewas poured into ethyl acetate (500 mL) and potassium carbonate solution(150 mL of a 2M aqueous solution), and shaken. The organic phase wasseparated, washed with water and brine, dried over solid potassiumcarbonate, and concentrated in vacuo to give 55.35 g (100% crude yield)of 4-((αR andαS)-α-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamideas a 1:1 mixture of isomers, epimeric at the benzhydryl carbon.

[0459] The allyl portion was removed using Pd(dba)₂/DPPB in the presenceof thiosalicylic acid by the method of Genet [J. P. Genet, S.Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270(1995)]. The reaction was concentrated and the residue was dissolved in300 mL ethyl acetate and 600 mL diethyl ether. After washing with Na₂CO₃solution (3×300 mL) and water (1×300 mL), the organic solution wasdiluted with pentane (1500 mL) and extracted with 3 M HCl (5×80 mL) and1 M HCl (3×100 mL), alternating with water (3×100 mL). The combinedaqueous extracts were filtered to remove a small amount of suspendedsolid and the pH was adjusted to 12 using 5M NaOH solution. Theresulting oily suspension was extracted with dichloromethane (3×300 mL).The combined organic solution was dried (Na₂SO₄/MgSO₄) and concentratedunder reduced pressure to give 4-((αR andαS)-α-((2R,5S)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamideas a pale yellow solid (27.11 g, 71.43 mmol). A solution of 4-((αR andαS)-α-((2R,5S)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide(27.11 g, 71.43 mmol) in acetonitrile (450 mL) was added to sodiumiodide (1.07 g, 7.14 mmol) and stirred under nitrogen at roomtemperature during the addition of triethylamine (35.84 mL, 26.02 g, 257mmol), followed by 3-fluorobenzyl bromide (17.52 mL, 143 mmol). Animmediate turbidity was observed on addition of the fluorobenzylbromide. The reaction mixture was stirred under nitrogen overnight atroom temperature. The solvent was removed by evaporation and the residuewas partitioned between 300 mL methylene chloride and 300 mL saturatedsodium bicarbonate solution, followed by extraction with another 2×300mL of methylene chloride. The combined organic extracts were washed withwater (2×300 mL), and brine (300 mL), dried over Na₂SO₄/MgSO₄ andconcentrated under reduced pressure. The residual deep-red oil waspurified by chromatography on silica gel (12% EtOAc in CH₂Cl₂) to give5.83 g (11.96 mmol) of4-((αS)-α-((2R,5S)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamideas a light yellow solid. The benzhydryl epimer,4-((αR)-α-((2R,5S)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide(5.46 g) and 11.25 g of the epimer mixture were also obtained. ¹H NMR(300 MHz, CDCl₃): δ 1.06-1.28 (m, 12H); 1.95-2.07 (m, 2H); 2.59-2.72 (m,4H); 3.22-3.55 (m, 5H); 3.81-3.86 (d, J=13.6 Hz, 1H); 5.11 (s, 1H);6.87-6.88 (t, 1H); 7.03-7.44 (m, 12H). Calculated for C₃₁H₃₈FN₃O.0.20EtOAc: C, 75.59; H, 7.90; N, 8.32; F, 3.76. Found: C, 75.53; H, 7.82; N,8.45; F, 3.69. HPLC: 91.85% by Ace C-18 (31t), initial 60% 0.01M NH₄OAcin MeOH: gradient to 100% MeOH, 60 min: isocratic MeOH 5 min. 0.7ml/min: λ_(obs)=210 nm, R_(t)=63.4 min for title compound. Thebenzyhydryl R epimer has R_(t)=62 min.

EXAMPLE 42

[0460](+)-3-((αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid

[0461](+)-3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide(Example 26) was dissolved in 95% ethanol containing 6% by weight ofsodium hydroxide and heated at reflux for 24 hours. The mixture wasconcentrated in vacuo to remove ethanol. The residue was dissolved inwater and the resulting solution was adjusted to pH 5 with concentratedhydrochloric acid. The solvent was removed in vacuo to give3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid as a mixture with sodium chloride. The crude acid was stirred witha small volume of water and filtered. The solid in the filter was washedwith water and dried under vacuum to give(+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoicacid as a light beige solid. NMR (DMSO-d₆, 200 MHz) δ: 0.95 (d, J=6 Hz,3H); 1.1 (d, J=6 Hz, 3H); 1.9 (ddd, J₁=3 Hz, J₂=7 Hz, J₃=10 Hz, 1H); 2.1(dd, J₁=8 Hz, J₂=10 Hz, 1H); 2.5 (m, 2H); 2.7-2.9 (m, 2H); 3.2 (m, 2H);5.05 (d, J=12 Hz, 1H); 5.2 (d, J=18 Hz, 1H); 5.8 (m, 1H); 6.7 (m, 3H);7.1 (t, J=8 Hz, 1H); 7.4 (t, J=8 Hz, 1H); 7.65 (d, J=8 Hz, 1H); 7.8 (d,J=8 Hz, 1H); 8.0 (s, 1H); 9.4 (s, 1H). [α]_(D) ²⁰=+4.1° (0.1 M aqueoussodium hydroxide, c=1.09). Calc. for C₂₃H₂₈N₂O₃ 0.75H₂O: C, 70.12; H,7.55; N, 7.11. Found: C, 70.23; H, 7.35; N, 7.10. Mass spectrum (C₁-CH₄)m/e: 381 (M+1, 35%); 380 (M, 2%); 227 (28%); 155 (100%); 153 (83%).

[0462] The following Examples 43-45 may be made by methods analogous tothose described in the preceding Examples.

EXAMPLE 43

[0463](3-{(R)-(3-Diethylcarbamoylphenyl)-[(2S,5R)-4-(3-hydroxybenzyl)-2,5-dimethylpiperazin-1-yl]methyl}-phenoxy)aceticacid

EXAMPLE 44

[0464](3-{(R)-(3-Diethylcarbamoylphenyl)-[(2S,5R)-4-(3-methoxybenzyl)-2,5-dimethylpiperazin-1-yl]methyl}-phenoxy)aceticacid

EXAMPLE 45

[0465] 5(3-1(2R,5S)-4-[(R)-(3-Carboxymethoxyphenyl)-(3-diethylcarbamoylphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}phenoxy)aceticacid

EXAMPLE 46

[0466] To investigate the efficacy of delta opioid receptor agonists asa treatment for premature ejaculation, intact conscious male mice wereelectrically stimulated subsequent to the administration of a deltaopioid receptor agonist to determine if a delay in ejaculation wasobserved when compared to administration of a placebo

[0467] General Materials and Methods

[0468] Male, CD-1 mice (20-30 g) were housed in groups of ten (10) inPlexiglas® chambers with food and water available before any procedure.Animals were maintained on a 12 hour light/dark cycle in atemperature-controlled animal colony. Studies were carried out inaccordance with the Guide for the Care and Use of Laboratory animals asadopted and promulgated by the National Institutes of Health.

[0469] An electric bipolar rectal probe, as shown in FIG. 1, was usedfor stimulating the subjects. Specifically, the bipolar electrode probeis an approximately 5 cm long tube having an outer diameter ofapproximately 0.25 cm with an inner diameter of approximately 0.08. Inthe center lumen of the elongated tubular body 12 are embedded cathode16 and anode 18, which are formed of a conductive material, preferablyplatinum. The cathode 16 and anode 18 are connected at one end toexternal power supplying means (not shown). Anode 18 extends at theother end all the way to one extremity of the elongated body 12 andforming an anode terminal 22 at such extremity. Cathode 16 only extendsto a middle portion of the elongated body 12 and forming a cathodeterminal 20 at such middle portion. The cathode terminal 20 ispreferably positioned away from the anode terminal 22, at a distance ofabout 0.5 cm.

[0470] The testing delta opioid receptor agonist (SNC-80) was purchasedfrom Tocris Cookson, Inc., Ellisville, Mo., USA, and dissolved in 5%dextrose injection solution. An equimolar amount of aqueous hydrochloricacid was added when the manufacturer packaged the compound in its baseform. The placebo was 5% dextrose alone. Each mouse was injectedsubcutaneously with 10 mg/kg of the SNC-80 compound or with 10 mg/kg ofa placebo. 10 minutes after the injection, the test mouse was subjectedto electrostimulation. Ten mice were tested for each dose level, theorder of each mouse receiving different doses was blinded and in arandom manner.

[0471] During the testing the mouse was restrained in a cone bag withrear legs extending from the bag. Excess fecal matter was removed fromthe rectum and the above-discussed lubricated bipolar electrode wasinserted approximately 2.5 cm into the rectum. An oscillating current of40 Hz was utilized for electrical stimulation starting at 3 volts with agradual increase to 8 volts by increments of 0.5 volts. The stimulationregime included 4 stimulating events for each voltage lasting 2 secondswith a rest period of 2 seconds between stimulating events untilejaculation occurred or the terminal voltage of 8 volts was reached. Awhite coagulum ejaculate from the penis indicates a successfulejaculation.

[0472] For the electroejaculation test, dose-response lines wereconstructed as an accumulated ejaculation at a specified voltage. Aminimum of 10 mice was used at each dose level. Each dose response wasthe average of two to three independent experiments. Students' t-testwas used to assess unpaired comparison, with p<0.06 indicatingsignificance.

[0473] Electric stimulation was conducted on untreated mice to determineeffective ejaculation parameters relating to current frequency andvoltage. It was found that when 10 mice were stimulated through thevoltage program starting at 3 volts with a gradual increase to 8 voltsby increments of 0.5 volts, none of the mice ejaculated if the currentfrequency was 20 Hz.

[0474] When the operating frequency increased from 30 to 70 Hz, theoccurrence of successful ejaculation, which is indicated by emission ofa white coagulum from the penis of the male mouse under stimulation,also increases. When the operating frequency of the electric stimulationwas between 30 to 45 Hz, the ejaculation rate showed a linear dependencyon the frequency. When the operating frequency reached 60 Hz, all themice ejaculated with a 100% ejaculation rate.

[0475] Testing was conducted on mice injected with SNC-80 or a buffervehicle for the control group. SNC-80 is a highly selective deltareceptor agonist which has been found to block the contraction of mousevas deferens smooth muscle in vitro which is one of the tissuecomponents in the ejaculation system. Each mouse was subjected toelectroejaculation at 40 Hz (starting at 3 volts with a gradual increaseto 8 volts by increments of 0.5 volts) approximately 10 minutes aftersubcutaneous administration of SNC-80 at different doses of 0, 0.1, 0.3and 1 mg/kg. A minimum of 10 mice were used at each dose level. Eachdoes response was the average of two to three independent experiments±SEM.

[0476] As shown in FIG. 3, when the frequency of the electricstimulation was set at 40 Hz, a dose of 1 mg/kg of SNC-80 significantlyreduced the occurrence of ejaculation in tested mice as compared to thatof the control group. This reduction of ejaculation by SNC-80 isspecific, as the compound works in a dose dependent manner and theinhibitory effect diminished as the concentration was reduced to 0.1mg/kg.

EXAMPLE 47

[0477] To determine if SNC-80 inhibits the ejaculation via specificbinding to delta opioid receptor, the effect of SNC-80 on ejaculationwas tested against the delta opioid selective antagonist naltrindole(NTI). Subcutaneous injections of a control vehicle (CTL), 0.5 mg/kgSNC-80, 0.5 mg/kg SNC-80 plus 0.1 mg/kg of NTI and 0.1 mg/kg of NTI wereadministered to the mice. A minimum of 10 mice was utilized for eachdose level. Each dose response is the average of two to threeindependent experiments ±SEM. Electroejaculation stimulation wasconducted 10 minutes after injection at 35 Hz oscillating frequency,starting at 3 volts with a gradual increase to 8 volts by increments of0.5 volts. As shown in FIG. 4, injection of 0.5 mg/kg of SNC-80 reducedthe ejaculation by a factor of at least 2. However, this inhibitoryeffect was blocked by co-injection with 0.1 mg/kg of NTI. This resultdemonstrated that blocking the delta opioid receptor by NTI eliminatedthe effect of SNC-80 on ejaculation, indicating that activation of thedelta opioid receptor reduced the electroejaculation in male mice. It isshown in FIG. 4 that injections of just NTI, without any other activeingredient, did not affect the ejaculation response.

EXAMPLE 48

[0478] Further evidence showing that activation of the delta opioidreceptor leads to reduction in ejaculation is shown by using additionaldelta opioid receptor agonists that were synthesized and formulated bythe inventors. Similar electroejaculation procedures were used accordingto Examples 46 and 47 to determine the efficacy in delayed ejaculation.All the compounds were found to be high affinity delta opioid receptoragonists as judged by radioligand competition binding and inhibition ofcontraction of mouse vas defens in tissue bath. As shown in Table 1, thecompounds displayed an inhibitory effect on male ejaculation. Theseresults further elucidate an inhibitory role of delta opioid receptoractivation in ejaculation. TABLE 1 Max. EC₅₀ ejaculation Optimal MVD¹Inhibition Dose² Example μ (nM)* δ (nM)* κ (nM)* (nM)** (%) (mg/kg) 1127.1 1.23 >100 2.8 30 5 12 1.45 0.123 68.7 4.4 28 5 14 162 11.1 >100 7.235 10 13 3470 5.69 >100 21.2 50 5 17 1.28 0.66 20.9 2.9 50 1

EXAMPLE 49

[0479] Additional formulations of delta opioid receptor agonists wereprepared and tested according to testing procedures set forth inExamples 46 and 47. The compounds were administered orally and theresults are compiled in Table 2. The results show that the delta opioidreceptor agonists had an inhibitory effect on ejaculation events of atleast 33%. TABLE 2 Effective Ejaculation Ex. Dose Inhibition Route ofCompound No. (mg/kg) % Admininstration3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5- 14 0.01 45% oraldimethyl-1-piperazinyl)-4-(diethyl amino-carbonyl)benzyl)phenoxyaceticacid 3-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5- 15 3 66% oraldimethyl-1-piperazinyl)-4-(diethyl aminocarbonyl)benzyl)phenoxyaceticacid 4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl- 29 3 38% oral4-(4-fluorobenzyl)-1-piperazinyl)-3- methoxybenzyl)-N,N-diethylbenzamide4-(alpha-R)-alpha-((2S,5R)-4-(Cyclo 35 0.3 60% oralpropylmethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl- 36 3 60% oral4-(3-fluorobenzyl)-1-piperazinyl)-3- hydroxybenzyl)-N,N-diethylbenzamide4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl- 37 3 50% oral4-(4-hydroxybenzyl)-1-piperazinyl)- benzyl)-N,N-diethylbenzamide4-(alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5- 38 3 33% oraldimethyl-1-piperazinyl)-3-methoxybenzyl)- N,N-diethylbenzamide4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl- 39 10 50% oral4-(2-fluorobenzyl)-1-piperazinyl)-3- methoxybenzyl)-N,N-diethylbenzamide4-[(R)-((2R,5S)-4-Allyl-2,5-dimethyl 40 0.3 50% oralpiperazin-1-yl)(3-hydroxyphenyl)methyl]- N,N-dimethylbenzenesulfonamide4-((alpha-S)-alpha-((2R,5S)-2,5-Dimethyl- 41 0.4 75% oral4-(3-fluorobenzyl)-1-piperazinyl)benzyl)- N,N-diethylbenzamide

EXAMPLE 50

[0480] Further evidence showing that activation of the delta opioidreceptor leads to reduction in ejaculation can be shown by usingadditional delta opioid receptor agonists as set forth in Table 3 below.Similar electroejaculation procedures are used according to Examples 46and 47 to determine the efficacy in delaying ejaculation. All thecompounds have been found to be delta opioid receptor agonists, and assuch, the use of the compounds results in inhibition of ejaculation inthe testing subjects. TABLE 3 EXAMPLE NO. STRUCTURE NAME 1

4-((alpha-S)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N- diethylbenzamide 2

4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide 3

4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N- diethylbenzamide 4

4-((alpha-S)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N- diethylbenzamide 5

4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)benzyl)-N,N- diethylbenzamide 6

4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-pyridylmethyl)-1-piperazinyl)benzyl)-N,N- diethylbenzamide 7

4-((alpha-S)-alpha-((2S,5R)-4-(3- Chlorobenzyl)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide 8

4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-methoxybenzyl)-1-piperazinyl)benzyl)- N,N-diethylbenzamide 16

3-((alpha-R)-4-(Diethylaminocarbonyl)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)benzyl)phenoxyacetic acid 18

(-)-4-(αR)-α-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl- benzamide 19

(-)-4-(αS)-α-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl- benzamide 20

(-)-4-((αR)-α-((2R,5R)-2,5-Dimethy1-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N- diethylbenzamide 21

(-)-4-(αS)-α-((2R,5R)-2,5-Dimethyl-4-propyl-piperazinyl)-3-hydroxybenzyl)-N,N- diethyl-benzamide 22

4-((αR)-α-(2S,5S)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-benzamide 23

(-)-3-((S)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol 24

3-((S)-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol 25

3-((S)-((2S,5R)-4-(2,6-Difluorobenzyl)-2,5- dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol 26

(+)-3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1piperazinyl)-3-hydroxybenzyl)-N-(3- fluorophenyl)-N-methylbenzamide 27

3-((R)-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3- fluorophenyl)-N-methylbenzamide 28

3-((R)-((2S,5R)-2,5-Dimethyl-4(4- fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N- methylbenzamide 30

N,N-Diethyl-3-[(R)-[2S,5R)-4-(3- hydroxybenzyl)-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]benzamide 31

N,N-Diethyl-3-{(R)-(3-hydroxyphenyl)- [(2S,5R)-4-(3-methoxybenzyl)-2,5-dimethylpiperazin-1-yl]methyl}benzamide 32

(3-{(2R,5S)-4-[(R)-(3-Diethylcarbamoyl-phenyl)-(3-hydroxyphenyl)methyl]-2,5- dimethyl-piperazin-1-ylmethyl}-phenoxy)acetic acid 33

(3-{(2R,5S)-4-[(R)-(3- Diethylcarbamoylphenyl)-(3-methoxyphenyl)methyl]-2,5- dimethylpiperazin-1-ylmethyl}phenoxy)aceticacid 34

N,N-Diethyl-3-[(R)-[(2S,5R)-4-(3-methoxybenzyl)-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]benzamide 42

(+)-3-((alpha-R)-alpha-((2S,5R)-4- Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoic acid 43

(3-{(R)-(3-Diethylcarbamoylphenyl)- [(2S,5R)-4-(3-hydroxybenzyl)-2,5-dimethylpiperazin-1-yl]methyl}- phenoxy)acetic acid 44

(3-{(R)-(3-Diethylcarbamoylphenyl)- [(2S,5R)-4-(3-methoxybenzyl)-2,5-dimethylpiperazin-1-yl]methyl}- phenoxy)acetic acid 45

(3-{(2R,5S)-4-[(R)-(3- Carboxymethoxyphenyl)-(3-diethylcarbamoylphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}phenoxy)acetic acid

[0481] While the invention has been described herein in reference tospecific aspects, features and illustrative embodiments of theinvention, it will be appreciated that the utility of the invention isnot thus limited, but rather extends to and encompasses numerous otheraspects, features and embodiments. Accordingly, the claims hereafter setforth are intended to be correspondingly broadly construed, as includingall such aspects, features and embodiments, within their spirit andscope.

What is claimed is:
 1. A method for delaying the onset of ejaculation ina subject, comprising administering a pharmaceutical formulationcomprising a delta receptor agonist in an amount effective to delay theonset of ejaculation in the subject during sexual stimulation.
 2. Themethod according to claim 1, wherein the pharmaceutical formulationfurther comprises at least one additional active agent.
 3. The methodaccording to claim 2, wherein the additional agent is selected from thegroup consisting of sildenafil citrate, fluoxetine, vasoactive agents,and combinations of two or more thereof.
 4. The method according toclaim 1, wherein the delta opioid receptor agonist comprises an agonistselected from the group consisting of: deltorphin I; deltorphin II;Biphalin; DADLE; [D-Ser², Leu⁵]enkephalil-Thr; and[D-Pen²,D-Pen⁵]-enkephalin.
 5. The method according to claim 1, whereinthe delta opioid receptor is an agonist selected from the groupconsisting of compounds of the formulae: (I)

wherein: Ar¹ is a 5- or 6-member carbocyclic or heterocyclic aromaticring with atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur and may include thiophenyl, thiazolyl, furanyl,pyrrolyl, phenyl, or pyridyl, and having on a first carbon atom thereofa substituent Y and on a second ring carbon thereof a substituent R, Yis selected from the group consisting of: hydrogen; halogen; C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy;C₃-C₆ cycloalkoxy; sulfides of the formula SR⁸ where R⁸ is C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, arylalkyl having aC₅-C₁₀ aryl moiety and an C₁-C₆ alkyl moiety, or C₅-C₁₀ aryl; sulfoxidesof the formula SOR⁸ where R⁸ is the same as above; sulfones of theformula SO₂R⁸ where R⁸ is the same as above; nitrile; C₁-C₆ acyl;alkoxycarbonylamino (carbamoyl) of the formula NHCO₂R⁸ where R⁸ is thesame as above; carboxylic acid, or an ester, amide, or salt thereof;aminomethyl of the formula CH₂NR⁹R¹⁰ where R⁹ and R¹⁰ may be the same ordifferent, and may be hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₂-C₆ hydroxyalkyl, C₂-C₆ methoxyalkyl, C₃-C₆ cycloalkyl, orC₅-C₁₀ aryl, or R⁹ and R¹⁰ together may form a ring of 5 or 6 atoms, thering atoms selected from the group consisting of N and C; carboxamidesof the formula CONR⁹R¹⁰ where R⁹ and R¹⁰ are the same as above, orC₂-C₃₀ peptide conjugates thereof; and sulfonamides of the formulaSO₂NR⁹R¹⁰ where R⁹ and R¹⁰ are the same as above; Z is selected from thegroup consisting of: hydrogen, hydroxy and carboxy and esters thereof;alkoxy, carboxyalkoxy, alkoxy-carboxylic acid, hydroxymethyl, and estersthereof; and amino, carboxamides and sulfonamides thereof; G is carbonor nitrogen; R¹ is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl; R² is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl; R³, R⁴ and R⁵ may be the same or different, and areindependently selected from hydrogen and methyl, and wherein at leastone of R³, R⁴ or R⁵ is not hydrogen, subject to the proviso that thetotal number of methyl groups does not exceed two, or any two of R³, R⁴and R⁵ together may form a bridge of 1 to 3 carbon atoms; R⁶ is selectedfrom the group consisting of: hydrogen; C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl; C₃-C₆ cycloalkyl; arylalkyl having C₅-C₁₀ aryl and C₁-C₆alkyl moieties; alkoxyalkyl having C₁-C₄ alkoxy and C₁-C₄ alkylmoieties; C₂-C₄ cyanoalkyl; C₂-C₄ hydroxyalkyl; aminocarbonylalkylhaving a C₁-C₄ alkyl moiety; and R¹²COR¹³, where R¹² is C₁-C₄ alkylene,and R¹³ is C₁-C₄ alkyl or C₁-C₄ alkoxy or hydroxy, or R⁶ is

and Ar¹ is a 5 or 6-member carbocyclic or heterocyclic aromatic ringwith atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur, and having on a carbon atom thereof a substituent X,wherein X is selected from the group consisting of a halogen (fluorine,bromine, chlorine, iodine), hydrogen, hydroxy, and esters thereof;carboxy and esters thereof; C₁-C₄ carboxyalkyl and esters thereof;alkoxy, carboxylic acid, alky carboxylic acid, hydroxymethyl, and estersthereof; and amino, and carboxamides and sulfonamides thereof, and R⁷ ishydrogen or fluorine; (II)

wherein R₁ and R₂, which can be the same or different, are eachhydrogen, linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkenyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, C₃₋₅ alkynyl, aryl,aralkyl or furan-2 or 3-yl alkyl. or may form together a C₃₋₇ alkyl ringwhich may be interrupted by oxygen. R₃ and R₄, which can be the same ordifferent, are each hydrogen, linear or branched C₁₋₆ alkyl, or R₄ isoxygen forming with the carbon atom to which is attached a C═O group; R₅is hydrogen, hydroxy, C₁₋₃ alkoxy, thiol or alkylthio; R₆ is phenyl,halogen, NH₂ or a para or meta —C(Z)—R₈ group, in which Z is oxygen orsulphur; R₈ is C₁₋₈-alkyl, C₁₋₈-alkoxy or NR₉R₁₀, wherein R₉ and R₁₀,which may be the same or different, are hydrogen, straight or branchedC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, aryl oraralkyl, or R₆ is a para or meta

 group in which R₁₁ and R₁₂ which may the same or different arehydrogen, straight or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆cycloalkylalkyl, C₃₋₆ alkenyl, aryl, aralkyl or an optionallysubstituted heterocyclic ring, and Z is as defined above; and, R₇ ishydrogen, straight or branched C₁₋₈ alkyl or halogen; (III)

wherein, R₁ and R₂, can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, C₄₋₆cycloalkylalkyl, C₃₋₆ alkenyl, C₃₋₅ alkynyl, aryl, aralkyl or furan-2 or3-yl alkyl or may form together a C₃₋₇ alkyl ring which may beinterrupted by oxygen. R₃ and R₄, can be the same or different, are eachhydrogen, linear or branched C₁₋₆ alkyl; R₅ is hydroxy, C₁₋₆ alkoxy,thiol or alkylthio; R₆ is a —C(Z)—R₈ group, wherein Z is oxygen orsulphur, R₈ is C₁₋₈-alkyl, C₁₋₈-alkoxy or NR₉R₁₀, wherein R₉ and R₁₀,which may be the same or different, are hydrogen, straight or branchedC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, aryl oraralkyl, or R₆ is a para or meta

 group wherein R₁₁ and R₁₂ have the same meaning as R₉ and R₁₀ ortogether form an optionally substituted heterocyclic ring and Z is asdefined above, and R₇ is hydrogen, straight or branched C₁₋₈ alkyl orhalogen; (IV)

wherein A is N or C—X wherein X is H or C₁₋₄ alkyl; G is C—Y wherein Yis H or C₁₋₄ alkyl; B is an optional C₁₋₆ hydrocarbyl group, optionallysubstituted; L is an optional C₁₋₆ hydrocarbyl group, optionallysubstituted; and wherein A, B, and L in combination with the Nconstitute a first ring structure which has from 5-7 atoms in the ring;further wherein: either D is H or a C₁₋₁₀ hydrocarbyl group, or D is aC₁₋₁₀ hydrocarbyl group linked to B or L to form a second ring structurewhich includes the N of the first ring structure, which second ringstructure is fused to the first ring structure and which second ringstructure has from 5-7 atoms in the ring; E is a phenyl groupsubstituted by at least one or more of hydroxy, C₁₋₄ alkoxy, or NH₂SO₂C₁₋₄ alkylene; F represents a combination of a phenyl group and aheterocyclic group, wherein (i) the phenyl group is positionedintermediate (in between) G and the heterocyclic group; (ii) the phenylgroup is fused to the heterocyclic group or is linked directly to theheterocyclic group or is attached via a spacer group to the heterocyclicgroup, wherein the spacer group is any one of C₁₋₄ alkylene, carbonyl orSO₂; and (iii) the heterocyclic group is substituted by at least one ormore of: a COOH group, a bio-isostere of a COOH group, a biolabile esterderivative of a COOH group, a C₁₋₁₀ hydrocarbyl group comprising one ormore COOH groups, a C₁₋₁₀ hydrocarbyl group comprising one or morebio-isosteres of a COOH group, or a C₁₋₁₀ hydrocarbyl group comprisingone or more biolabile ester derivatives of a COOH group; andpharmaceutically acceptable esters and salts of compounds (I)-(IV). 6.The method of claim 5, wherein the compound is administered by anadministration modality selected from the group consisting of oral,rectal, topical, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous,intramuscular, intravenous, transdermal, spinal, ransurethral,intrathecal, intra-articular, intra-arterial, sub-arachnoid, bronchialand lymphatic administration.
 7. The method of claim 5, wherein thecompound is administered in an oral unitary dose form.
 8. Apharmaceutical composition for delaying the onset of ejaculation in asubject, comprising a delta receptor agonist compound in an amount toeffectively delay the onset of ejaculation in the subject during sexualstimulation, and at least one additional active agent.
 9. Thecomposition of claim 8, wherein the delta receptor agonist compound isselected from the group consisting of compounds of the formulae: (I)

wherein: Ar¹ is a 5- or 6-member carbocyclic or heterocyclic aromaticring with atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur, and having on a first carbon atom thereof asubstituent Y and on a second ring carbon thereof a substituent R¹, Y isselected from the group consisting of: hydrogen; halogen; C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₃-C₆cycloalkoxy; sulfides of the formula SR⁸ where R⁸ is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, arylalkyl having a C₅-C₁₀ arylmoiety and an C₁-C₆ alkyl moiety, or C₅-C₁₀ aryl; sulfoxides of theformula SOR⁸ where R⁸ is the same as above; sulfones of the formulaSO₂R⁸ where R⁸ is the same as above; nitrile; C₁-C₆ acyl;alkoxycarbonylamino (carbamoyl) of the formula NHCO₂R⁸ where R⁸ is thesame as above; carboxylic acid, or an ester, amide, or salt thereof;aminomethyl of the formula CH₂NR⁹R¹⁰ where R⁹ and R¹⁰ may be the same ordifferent, and may be hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₂-C₆ l hydroxyalkyl, C₂-C₆ methoxyalkyl, C₃-C₆ cycloalkyl, orC₅-C₁₀ aryl, or R⁹ and R¹⁰ together may form a ring of 5 or 6 atoms, thering atoms selected from the group consisting of N and C; carboxamidesof the formula CONR⁹R¹⁰ where R⁹ and R¹⁰ are the same as above, orC₂-C₃₀ peptide conjugates thereof; and sulfonamides of the formulaSO₂NR⁹R¹⁰ where R⁹ and R¹⁰ are the same as above; Z is selected from thegroup consisting of: hydrogen, hydroxy and carboxy and esters thereof;alkoxy, carboxyalkoxy, alkoxy-carboxylic acid, hydroxymethyl, and estersthereof; and amino, carboxamides and sulfonamides thereof; G is carbonor nitrogen; R¹ is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl; R² is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl; R³, R⁴ and R⁵ may be the same or different, and areindependently selected from hydrogen and methyl, and wherein at leastone of R³, R⁴ or R⁵ is not hydrogen, subject to the proviso that thetotal number of methyl groups does not exceed two, or any two of R³, R⁴and R⁵ together may form a bridge of 1 to 3 carbon atoms; R⁶ is selectedfrom the group consisting of: hydrogen; C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl; C₃-C₆ cycloalkyl; arylalkyl having C₅-C₁₀ aryl and C₁-C₆alkyl moieties; alkoxyalkyl having C₁-C₄ alkoxy and C₁-C₄ alkylmoieties; C₂-C₄ cyanoalkyl; C₂-C₄ hydroxyalkyl; aminocarbonylalkylhaving a C₁-C₄ alkyl moiety; and R¹²COR¹³, where R¹² is C₁-C₄ alkylene,and R¹³ is C₁-C₄ alkyl or C₁-C₄ alkoxy or hydroxy, or R⁶ is

and Ar² is a 5 or 6-member carbocyclic or heterocyclic aromatic ringwith atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur, and having on a carbon atom thereof a substituent X,wherein X is selected from the group consisting of a halogen (fluorine,bromine, chlorine, iodine), hydrogen, hydroxy, and esters thereof;carboxy and esters thereof; C₁-C₄ carbosyalkyl and esters thereof;alkoxy, carboxylic acid, alkyl carboxylic acid, hydroxymethyl, andesters thereof; and amino, and carboxamides and sulfonamides thereof;and R⁷ is hydrogen or fluorine; (II)

wherein R₁ and R₂, which can be the same or different, are eachhydrogen, linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkenyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, C₃₋₅ alkynyl, aryl,aralkyl or furan-2 or 3-yl alkyl or may form together a C₃₋₇ alkyl ringwhich may be interrupted by oxygen. R₃ and R₄, which can be the same ordifferent, are each hydrogen, linear or branched C₁₋₆ alkyl, or R₄ isoxygen forming with the carbon atom to which is attached a C═O group; R₅is hydrogen, hydroxy, C₁₋₃ alkoxy, thiol or alkylthio; R₆ is phenyl,halogen, NH₂ or a para or meta —C(Z)—R₈ group, in which Z is oxygen orsulphur; R₈ is C₁₋₈-alkyl, C₁₋₈-alkoxy or NR₉R₁₀, wherein R₉ and R₁₀,which may be the same or different, are hydrogen, straight or branchedC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, aryl oraralkyl, or R₆ is a para or meta

group in which R₁₁ and R₁₂ which may the same or different are hydrogen,straight or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkylalkyl,C₃₋₆ alkenyl, aryl, aralkyl or an optionally substituted heterocyclicring, and Z is as defined above; and, R₇ is hydrogen, straight orbranched C₁₋₈ alkyl or halogen; (III)

wherein, R₁ and R₂, can be the same or different, are each hydrogen,linear or branched C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, C₄₋₆cycloalkylalkyl, C₃₋₆ alkenyl, C₃₋₅ alkynyl, aryl, aralkyl or furan-2 or3-yl alkyl or may form together a C₃₋₇ alkyl ring which may beinterrupted by oxygen. R₃ and R₄, can be the same or different, are eachhydrogen, linear or branched C₁₋₆ alkyl; R₅ is hydroxy, C₁₋₆ alkoxy,thiol or alkylthio; R₆ is a —C(Z)—R₈ group, wherein Z is oxygen orsulphur, R₈ is C₁₋₈-alkyl, C₁₋₈-alkoxy or NR₉R₁₀, wherein R₉ and R₁₀,which may be the same or different, are hydrogen, straight or branchedC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkylalkyl, C₃₋₆ alkenyl, aryl oraralkyl, or R₆ is a para or meta

group wherein R₁₁ and R₁₂ have the same meaning as R₉ and R₁₀ ortogether form an optionally substituted heterocyclic ring and Z is asdefined above, and R₇ is hydrogen, straight or branched C₁₋₈ alkyl orhalogen; and (IV)

wherein A is N or C—X wherein X is H or C₁₋₄ alkyl; G is C—Y wherein Yis H or C₁₋₄ alkyl; B is an optional C₁₋₆ hydrocarbyl group, optionallysubstituted; L is an optional C₁₋₆ hydrocarbyl group, optionallysubstituted; and wherein A, B, and L in combination with the Nconstitute a first ring structure which has from 5-7 atoms in the ring;further wherein: either D is H or a C₁₋₁₀ hydrocarbyl group, or D is aC₁₋₁₀ hydrocarbyl group linked to B or L to form a second ring structurewhich includes the N of the first ring structure, which second ringstructure is fused to the first ring structure and which second ringstructure has from 5-7 atoms in the ring; E is a phenyl groupsubstituted by at least one or more of hydroxy, C₁₋₄ alkoxy, or NH 2 SO₂C₁₋₄ alkylene; F represents a combination of a phenyl group and aheterocyclic group, wherein (i) the phenyl group is positionedintermediate (in between) G and the heterocyclic group; (ii) the phenylgroup is fused to the heterocyclic group or is linked directly to theheterocyclic group or is attached via a spacer group to the heterocyclicgroup, wherein the spacer group is any one of C₁₋₄ alkylene, carbonyl orSO₂; and (iii) the heterocyclic group is substituted by at least one ormore of: a COOH group, a bio-isostere of a COOH group, a biolabile esterderivative of a COOH group, a C₁₋₁₀ hydrocarbyl group comprising one ormore COOH groups, a C₁₋₁₀ hydrocarbyl group comprising one or morebio-isosteres of a COOH group, or a C₁₋₁₀ hydrocarbyl group comprisingone or more biolabile ester derivatives of a COOH group; andpharmaceutically acceptable esters and salts of compounds (I)-(IV). 10.The composition of claim 8, wherein the delta receptor agonist compoundcomprises an agonist selected from the group consisting of: deltorphinI; deltorphin II; DADLE; Biphalin; [D-Ser², Leu⁵]enkephalin-Thr; and[D-Pen²,D-Pen⁵]-enkephalin.
 11. A method of damping male sexual responsecomprising administering to a subject in need thereof, an effectivesexual response damping amount of a delta opioid receptor agonist.
 12. Amethod of effecting diminution of libido in a subject in need thereof,comprising administering to a subject in need thereof, an effectivediminution of libido amount of a delta opioid receptor agonist.
 13. Amethod for delaying the onset of ejaculation in a subject, comprisingadministering a pharmaceutical formulation comprising a delta opioidreceptor agonist in an amount effective to delay the onset ofejaculation in the subject during sexual stimulation, wherein the deltaopioid receptor agonist is of the general formula:

wherein: Ar¹ is a 5- or 6-member carbocyclic or heterocyclic aromaticring with atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur and may include thiophenyl, thiazolyl, furanyl,pyrrolyl, phenyl, or pyridyl, and having on a first carbon atom thereofa substituent Y and on a second ring carbon thereof a substituent R¹, Yis selected from the group consisting of: hydrogen; halogen; C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy;C₃-C₆ cycloalkoxy; sulfides of the formula SR⁸ where R⁸ is C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, arylalkyl having aC₅-C₁₀ aryl moiety and an C₁-C₆ alkyl moiety, or C₅-C₁₀ aryl; sulfoxidesof the formula SOR⁸ where R⁸ is the same as above; sulfones of theformula SO₂R⁸ where R⁸ is the same as above; nitrile; C₁-C₆ acyl;alkoxycarbonylamino (carbamoyl) of the formula NHCO₂R₈ where R₉ is thesame as above; carboxylic acid, or an ester, amide, or salt thereof;aminomethyl of the formula CH₂NR⁹R¹⁰ where R⁹ and R¹⁰ may be the same ordifferent, and may be hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₂-C₆ hydroxyalkyl, C₂-C₆ methoxyalkyl, C₃-C₆ cycloalkyl, orC₅-C₁₀ aryl, or R⁹ and R¹⁰ together may form a ring of 5 or 6 atoms, thering atoms selected from the group consisting of N and C; carboxamidesof the formula CONR⁹R¹⁰ where R⁹ and R¹⁰ are the same as above, orC₂-C₃₀ peptide conjugates thereof; and sulfonamides of the formulaSO₂NR⁹R¹⁰ where R⁹ and R¹⁰ are the same as above; Z is selected from thegroup consisting of: hydrogen, hydroxy and carboxy and esters thereof;alkoxy, carboxyalkoxy, alkoxy-carboxylic acid, hydroxymethyl, and estersthereof; and amino, carboxamides and sulfonamides thereof; G is carbonor nitrogen; R¹ is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl; R² is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl; R³, R⁴ and R⁵ may be the same or different, and areindependently selected from hydrogen and methyl, and wherein at leastone of R³, R⁴ or R⁵ is not hydrogen, subject to the proviso that thetotal number of methyl groups does not exceed two, or any two of R³, R⁴and R⁵ together may form a bridge of 1 to 3 carbon atoms; R⁶ is selectedfrom the group consisting of: hydrogen; C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl; C₃-C₆ cycloalkyl; arylalkyl having C₅-C₁₀ aryl and C₁-C₆alkyl moieties; alkoxyalkyl having C₁-C₄ alkoxy and C₁-C₄ alkylmoieties; C₂-C₄ cyanoalkyl; C₂-C₄ hydroxyalkyl; aminocarbonylalkylhaving a C₁-C₄ alkyl moiety; and R¹²COR¹³, where R¹² is C₁-C₄ alkylene,and R¹³ is C₁-C₄ alkyl or C₁-C₄ alkoxy or hydroxy, or R⁶ is

and Ar² is a 5 or 6-member carbocyclic or heterocyclic aromatic ringwith atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur, and having on a carbon atom thereof a substituent X,wherein X is selected from the group consisting of a halogen (fluorine,bromine, chlorine, iodine), hydrogen, hydroxy, and esters thereof;carboxy and esters thereof; C₁-C₄ carboxyalkyl and esters thereof;alkoxy, carboxylic acid, alky carboxylic acid, hydroxymethyl, and estersthereof; and amino, and carboxamides and sulfonamides thereof; and R⁷ ishydrogen or fluorine; or a pharmaceutically acceptable ester or saltthereof.
 14. The method of claim 13, wherein the delta opioid receptoragonist is administered to the subject in a dosage amount of from about1 mg to about 50 mg per kilogram body weight per day.
 15. The method ofclaim 14, wherein the administration is by oral administration.
 16. Themethod of claim 13, wherein the delta opioid receptor agonist is3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylamino-carbonyl)benzyl)phenoxyacetic acid.
 17. The method of claim 13, wherein the delta opioidreceptor agonist is3-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-4-(diethylaminocarbonyl)benzyl)phenoxyacetic acid.
 18. The method of claim 13, wherein the delta opioidreceptor agonist is4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide.19. The method of claim 13, wherein the delta opioid receptor agonist is4-(alpha-R)-alpha-((2S,5R)-4-(Cyclopropylmethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.20. The method of claim 13, wherein the delta opioid receptor agonist is4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.21. The method of claim 13, wherein the delta opioid receptor agonist is4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl)-benzyl)-N,N-diethylbenzamide.22. The method of claim 13, wherein the delta opioid receptor agonist is4-(alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide.23. The method of claim 13, wherein the delta opioid receptor agonist is4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide.24. The method of claim 13, wherein the delta opioid receptor agonist is4-[(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide.25. The method of claim 13, wherein the delta opioid receptor agonist is4-((alpha-R)-alpha-((2R,5S)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide.26. The method of claim 13, wherein the delta opioid receptor agonist is4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.27. The method of claim 13, wherein the delta opioid receptor agonist is4-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.28. The method of claim 13, wherein the delta opioid receptor agonist is4-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoicacid.
 29. The method of claim 13, wherein the delta opioid receptoragonist isN,N-Diethyl-3-((R)-((2S,5R)-2,5-dimethyl-4-(3-hydroxybenzyl)piperazin-1-yl)(3-hydroxyphenyl)methyl)benzamide.30. The method of claim 13, wherein the delta opioid receptor agonist isa member selected from the group consisting of:3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylamino-carbonyl)benzyl)phenoxyaceticacid;3-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-4-diethylaminocarbonyl)benzyl)phenoxyacetic acid;4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide;4-(alpha-R)-alpha-((2S,5R)-4-(Cyclopropylmethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl)-benzyl)-N,N-diethylbenzamide;4-(alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide;4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide;4-[(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide;4-((alpha-R)-alpha-((2R,5S)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide;4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;4-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;4-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoic acid;N,N-Diethyl-3-((R)-((2S,5R)-2,5-dimethyl-4-(3-hydroxybenzyl)piperazin-1-yl)(3-hydroxyphenyl)methyl)benzamide; and a pharmaceutically acceptable ester or saltthereof.
 31. The method of claim 30, wherein the delta opioid receptoragonist is orally administrable.
 32. The method according to claim 30,wherein the pharmaceutical formulation further comprises at least oneadditional active agent.
 33. The method according to claim 32, whereinthe additional agent comprises a member selected from the groupconsisting of sildenafil citrate, fluoxetine, vasoactive agents, andcombinations of two or more thereof.
 34. The method of claim 30, whereinthe compound is administered by an administration modality selected fromthe group consisting of oral, rectal, topical, sub-lingual, mucosal,nasal, ophthalmic, subcutaneous, intramuscular, intravenous,transdermal, transurethral spinal, intrathecal, intra-articular,intra-arterial, sub-arachnoid, bronchial and lymphatic.
 35. The methodof claim 30, wherein the compound is administered in an oral unitarydose form.
 36. The method according to claim 30, wherein the deltaopioid receptor agonist is administered to the subject in a dosageamount of from about 1 mg to about 50 mg per kilogram body weight perday.
 37. The method according to claim 30, wherein the delta opioidreceptor agonist is administered to the subject in a dosage amount offrom about 10 ug to 500 mg per kg of body weight of the subject per day.38. The method according to claim 30, wherein the delta opioid receptoragonist is administered to the subject in a dosage amount of from about50 μg to 75 mg per kilogram of body weight per day.
 39. A pharmaceuticalcomposition for delaying the onset of ejaculation in a subject,comprising a delta opioid receptor agonist compound in an amount toeffectively delay the onset of ejaculation in the subject during sexualstimulation, and at least one additional active agent, wherein the deltaopioid receptor agonist wherein the delta opioid receptor agonist is ofthe general formula:

wherein: Ar¹ is a 5- or 6-member carbocyclic or heterocyclic aromaticring with atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur and may include thiophenyl, thiazolyl, furanyl,pyrrolyl, phenyl, or pyridyl, and having on a first carbon atom thereofa substituent Y and on a second ring carbon thereof a substituent R¹, Yis selected from the group consisting of: hydrogen; halogen; C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy;C₃-C₆ cycloalkoxy; sulfides of the formula SR⁸ where R⁸ is C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, arylalkyl having aC₅-C₁₀ aryl moiety and an C₁-C₆ alkyl moiety, or C₅-C₁₀ aryl; sulfoxidesof the formula SOR⁸ where R⁸ is the same as above; sulfones of theformula SO₂R⁸ where R⁸ is the same as above; nitrile; C₁-C₆ acyl;alkoxycarbonylamino (carbamoyl) of the formula NHCO₂R⁸ where R⁸ is thesame as above; carboxylic acid, or an ester, amide, or salt thereof;aminomethyl of the formula CH₂NR⁹R¹⁰ where R⁹ and R¹⁰ may be the same ordifferent, and may be hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₂-C₆ hydroxyalkyl, C₂-C₆ methoxyalkyl, C₃-C₆ cycloalkyl, orC₅-C₁₀aryl, or R⁹ and R¹⁰ together may form a ring of 5 or 6 atoms, thering atoms selected from the group consisting of N and C; carboxamidesof the formula CONR⁹R¹⁰ where R⁹ and R¹⁰ are the same as above, orC₂-C₃₀ peptide conjugates thereof; and sulfonamides of the formulaSO₂NR⁹R¹⁰ where R⁹ and R¹⁰ are the same as above; Z is selected from thegroup consisting of: hydrogen, hydroxy and carboxy and esters thereof;alkoxy, carboxyalkoxy, alkoxy-carboxylic acid, hydroxymethyl, and estersthereof; and amino, carboxamides and sulfonamides thereof; G is carbonor nitrogen; R¹ is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl; R² is hydrogen, halogen, or C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl; R³, R⁴ and R⁵ may be the same or different, and areindependently selected from hydrogen and methyl, and wherein at leastone of R³, R⁴ or R⁵ is not hydrogen, subject to the proviso that thetotal number of methyl groups does not exceed two, or any two of R³, R⁴and R⁵ together may form a bridge of 1 to 3 carbon atoms; R⁶ is selectedfrom the group consisting of: hydrogen; C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl; C₃-C₆ cycloalkyl; arylalkyl having C₅-C₁₀ aryl and C₁-C₆alkyl moieties; alkoxyalkyl having C₁-C₄ alkoxy and C₁-C₄ alkylmoieties; C₂-C₄ cyanoalkyl; C₂-C₄ hydroxyalkyl; aminocarbonylalkylhaving a C₁-C₄ alkyl moiety; and R¹²COR¹³, where R¹² is C₁-C₄ alkylene,and R¹³ is C₁-C₄ alkyl or C₁-C₄ alkoxy or hydroxy, or R⁶ is

and Ar² is a 5 or 6-member carbocyclic or heterocyclic aromatic ringwith atoms selected from the group consisting of carbon, nitrogen,oxygen and sulfur, and having on a carbon atom thereof a substituent X,wherein X is selected from the group consisting of a halogen (fluorine,bromine, chlorine, iodine), hydrogen, hydroxy, and esters thereof;carboxy and esters thereof; C₁-C₄ carboxyalkyl and esters thereof;alkoxy, carboxylic acid, alky carboxylic acid, hydroxymethyl, and estersthereof; and amino, and carboxamides and sulfonamides thereof; and R⁷ ishydrogen or fluorine; or a pharmaceutically acceptable ester or saltthereof.
 40. The pharmaceutical composition of claim 39, wherein thedelta opioid receptor agonist is administered to the subject in a dosageamount of from about 1 mg to about 50 mg per kilogram body weight perday.
 41. The pharmaceutical composition of claim 39, wherein theadministration is by oral administration.
 42. The pharmaceuticalcomposition of claim 39, wherein the delta opioid receptor agonist is3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylaminocarbonyl)benzyl)phenoxyacetic acid.
 43. The pharmaceutical composition of claim 39,wherein the delta opioid receptor agonist is3-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-4-(diethylaminocarbonyl)benzyl)phenoxyacetic acid.
 44. The pharmaceutical composition of claim 39,wherein the delta opioid receptor agonist is4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide.45. The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is4-(alpha-R)-alpha-((2S,5R)-4-(Cyclopropylmethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.46. The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.47. The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl)-benzyl)-N,N-diethylbenzamide.48. The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is4-(alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide.49. The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide.50. The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is4-[(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide.
 51. The pharmaceutical composition of claim 39, wherein thedelta opioid receptor agonist is4-((alpha-R)-alpha-((2R,5S)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide.52. The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.53 The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is4-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide.54. The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is4-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoicacid.
 55. The pharmaceutical composition of claim 39, wherein the deltaopioid receptor agonist isN,N-Diethyl-3-((R)-((2S,5R)-2,5-dimethyl-4-(3-hydroxybenzyl)piperazin-1-yl)(3-hydroxyphenyl)methyl)benzamide.56. The pharmaceutical composition of claim 39, wherein the delta opioidreceptor agonist is a member selected from the group consisting of:3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylaminocarbonyl)benzyl)phenoxyaceticacid;3-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-4-diethylaminocarbonyl)benzyl)phenoxyacetic acid;4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide;4-(alpha-R)-alpha-((2S,5R)-4-(Cyclopropylmethyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl)-benzyl)-N,N-diethylbenzamide;4-(alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide;4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide;4-[(R)-((2R,5S)-4-Allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide;4-((alpha-R)-alpha-((2R,5S)-2,5-Dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide;4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;4-((alpha-R)-alpha-((2S,5R)-4-Benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;4-{(2R,5S)-4-[(R)-(4-Diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethylpiperazin-1-ylmethyl}benzoic acid; andN,N-Diethyl-3-((R)-((2S,5R)-2,5-dimethyl-4-(3-hydroxybenzyl)piperazin-1-yl)(3-hydroxyphenyl)methyl)benzamide.
 57. The pharmaceutical composition of claim 56,wherein the pharmaceutical composition is orally administrable.
 58. Thepharmaceutical composition according to claim 39, wherein the additionalagent is selected from the group consisting of sildenafil citrate,fluoxetine, vasoactive agents, and combinations of two or more thereof.59. The pharmaceutical composition of claim 56, wherein the compound isadministered by an administration modality selected from the groupconsisting of oral, rectal, topical, sub-lingual, mucosal, nasal,ophthalmic, subcutaneous, intramuscular, intravenous, transdermal,transurethral spinal, intrathecal, intra-articular, intra-arterial,sub-arachnoid, bronchial and lymphatic.
 60. The pharmaceuticalcomposition of claim 59, wherein the compound is administered in aunitary dose form.
 61. The pharmaceutical composition of claim 56,wherein the delta opioid receptor agonist is administered to the subjectin a dosage amount of from about 1 mg to about 50 mg per kilogram bodyweight per day.
 62. The pharmaceutical composition of claim 56, whereinthe delta opioid receptor agonist is administered to the subject in adosage amount of from about 10 ug to 500 mg per kg of body weight of thesubject per day.
 63. The pharmaceutical composition of claim 56, whereinthe delta opioid receptor agonist is administered to the subject in adosage amount of from about 50 μg to 75 mg per kilogram of body weightper day.